MemoryMuisti: juni 2019

tisdag 25 juni 2019

Insuliini ja autofagia neurodegeneraatiossa (2019t ietoa)

https://www.frontiersin.org/articles/10.3389/fnins.2019.00491/full

söndag 23 juni 2019

Proliinisykli syöpäterapian kohteena 2018

Format: Abstract

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2018 Jun 26;57(25):3433-3444. doi: 10.1021/acs.biochem.8b00215. Epub 2018 Apr 23.

The Proline Cycle As a Potential Cancer Therapy Target.

Tanner JJ, Fendt SM^1,², Becker DF³.

Abstract

Interest in how proline contributes to cancer biology is expanding because of the emerging role of a novel proline metabolic cycle in cancer cell survival, proliferation, and metastasis. Proline biosynthesis and degradation involve the shared intermediate Δ¹-pyrroline-5-carboxylate (P5C), which forms l-glutamate-γ-semialdehyde (GSAL) in a reversible non-enzymatic reaction. Proline is synthesized from glutamate or ornithine through GSAL/P5C, which is reduced to proline by P5C reductase (PYCR) in a NAD(P)H-dependent reaction. The degradation of proline occurs in the mitochondrion and involves two oxidative steps catalyzed by proline dehydrogenase (PRODH) and GSAL dehydrogenase (GSALDH). PRODH is a flavin-dependent enzyme that couples proline oxidation with reduction of membrane-bound quinone, while GSALDH catalyzes the NAD⁺-dependent oxidation of GSAL to glutamate. PRODH and PYCR form a metabolic relationship known as the proline-P5C cycle, a novel pathway that impacts cellular growth and death pathways. The proline-P5C cycle has been implicated in supporting ATP production, protein and nucleotide synthesis, anaplerosis, and redox homeostasis in cancer cells. This Perspective details the structures and reaction mechanisms of PRODH and PYCR and the role of the proline-P5C cycle in cancer metabolism. A major challenge in the field is to discover inhibitors that specifically target PRODH and PYCR isoforms for use as tools for studying proline metabolism and the functions of the proline-P5C cycle in cancer. These molecular probes could also serve as lead compounds in cancer drug discovery targeting the proline-P5C cycle.

PMID:: 29648801
PMCID:: PMC6026536; [Available on 2019-06-26]
DOI:: 10.1021/acs.biochem.8b00215

[Indexed for MEDLINE]

P5CS, D1-pyrroline-5-carboxylate synthetase ALDH18A1 (10q24.19

https://www.ncbi.nlm.nih.gov/gene

Official Symbol: ALDH18A1
Official Full Name: aldehyde dehydrogenase 18 family member A1

Also known as: GSAS; P5CS; PYCS; SPG9; ADCL3; SPG9A; SPG9B; ARCL3A
Summary: This gene is a member of the aldehyde dehydrogenase family and encodes a bifunctional ATP- and NADPH-dependent mitochondrial enzyme with both gamma-glutamyl kinase and gamma-glutamyl phosphate reductase activities. The encoded protein catalyzes the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine. Mutations in this gene lead to hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia and may be associated with neurodegeneration, cataracts and connective tissue diseases. Alternatively spliced transcript variants, encoding different isoforms, have been described for this gene. [provided by RefSeq, Jul 2008]
Expression Ubiquitous expression in duodenum (RPKM 41.4), small intestine (RPKM 34.7) and 25 other tissues See more
Orthologs mouse all

Preferred Names: delta-1-pyrroline-5-carboxylate synthase

Names: Spastic paraplegia-9 (spastic paraparesis with amyotrophy, cataracts and gastroesophageal reflux); aldehyde dehydrogenase family 18 member A1; delta-1-pyrroline-5-carboxylate synthetase; delta1-pyrroline-5-carboxlate synthetase; pyrroline-5-carboxylate synthetase (glutamate gamma-semialdehyde synthetase); spastic paraplegia 9 (autosomal dominant)

NP_001017423.1

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PYCR2(1q42.12)

https://www.ncbi.nlm.nih.gov/gene/29920

Official Symbol: PYCR2provided by HGNC
Official Full Name: pyrroline-5-carboxylate reductase 2provided by HGNC
Also known as: HLD10; P5CR2
Summary: This gene belongs to the pyrroline-5-carboxylate reductase family. The encoded mitochondrial protein catalyzes the conversion of pyrroline-5-carboxylate to proline, which is the last step in proline biosynthesis. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Nov 2012]
Expression: Ubiquitous expression in adrenal (RPKM 27.1), spleen (RPKM 24.2) and 25 other tissues See more
Orthologs

Preferred Names: pyrroline-5-carboxylate reductase 2

Names: P5C reductase 2; pyrroline 5-carboxylate reductase isoform; pyrroline-5-carboxylate reductase family member 2

FEATURES             Location/Qualifiers
     source          1..246
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="1"
                     /map="1q42.12"
     Protein         1..246
                     /product="pyrroline-5-carboxylate reductase 2 isoform 2"
                     /EC_number="1.5.1.2"
                     /note="pyrroline 5-carboxylate reductase isoform; P5C
                     reductase 2; pyrroline-5-carboxylate reductase family
                     member 2"
                     /calculated_mol_wt=25737
     Region          1..194
                     /region_name="P5CR_dimer"
                     /note="Pyrroline-5-carboxylate reductase dimerisation;
                     cl25964"
                     /db_xref="CDD:330785"
     CDS             1..246
                     /gene="PYCR2"
                     /gene_synonym="HLD10; P5CR2"
                     /coded_by="NM_001271681.1:231..971"
                     /note="isoform 2 is encoded by transcript variant 2"
                     /db_xref="CCDS:CCDS73039.1"
                     /db_xref="GeneID:29920"
                     /db_xref="HGNC:HGNC:30262"
                     /db_xref="MIM:616406"
ORIGIN      
        1 msvgfigagq layalargft aagilsahki iasspemnlp tvsalrkmgv nltrsnketv
       61 khsdvlflav kphiipfild eigadvqarh ivvscaagvt issvekafma ldaladggvk
      121 mglprrlaiq lgaqallgaa kmlldseqhp cqlkdnvcsp ggatihalhf lesggfrsll
      181 inaveascir trelqsmadq ekispaalkk tlldrvkles ptvstltpss pgklltrsla
      241 lggkkd
//

GeneRIFs: Gene References Into Functions

PYCR1 ( 17q25.31) pyrroline-5-carboxylate reductase 1

https://www.ncbi.nlm.nih.gov/gene/5831

Official Symbol: PYCR1provided by HGNC
Official Full Name: pyrroline-5-carboxylate reductase 1provided by HGNC
Also known as: P5C; P5CR; PRO3; PYCR; PIG45; PP222; ARCL2B; ARCL3B
Summary: This gene encodes an enzyme that catalyzes the NAD(P)H-dependent conversion of pyrroline-5-carboxylate to proline. This enzyme may also play a physiologic role in the generation of NADP(+) in some cell types. The protein forms a homopolymer and localizes to the mitochondrion. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]
Expression Broad expression in salivary gland (RPKM 19.9), stomach (RPKM 16.0) and 19 other tissues See more Orthologs mouse all

Preferred Names: pyrroline-5-carboxylate reductase 1, mitochondrial

Names: P5C reductase 1; proliferation-inducing protein 45

https://www.ncbi.nlm.nih.gov/protein/NP_001269208.1

ORIGIN      
        1 msvgfigagq lafalakgft aagvlaahki masspdmdla tvsalrkmgv kltphnketv
       61 qhsdvlflav kphiipfild eigadiedrh ivvscaagvt issiekklsa frpaprvirc
      121 mtntpvvvre gatvyatgth aqvedgrlme qllssvgfct eveedlidav tglsgsgpay
      181 gaakmllhse qhpgqlkdnv sspggatiha lhvlesggfr sllinaveas cirtrelqsm
      241 adqeqvspaa ikktildkvk ldspagtals psghtkllpr slapagkd
//

Conserved Domains (1) summary

cl25964 Location:1 → 237: P5CR_dimer; Pyrroline-5-carboxylate reductase dimerisation

GeneRIFs: Gene References Into Functions

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Proliinista glutamiinihapoksi tien vaikeuksia

Tuli mieleen Harperin kartta Pro-Glu- ja Pro-Arg tiestä. Ataxiini2.n peptidisekvenssissä on aluksi glutamiinihappoa ja histidiiniä, muta siten muuttuu tasapino ja alkaa tulla yhäenemmän proliinia ja lopulta pq ja qq ilmenemiä. Siis proliinista takaisin arginiiniin ja glutamiinihappoon oleva tie ei toimi riittävästi, joten paljon arginiinia vaativa proliinidehydrogenaasi ei pääse toimimaan ja tuotamaan E ja R , joten on myös liikaa anmmoniumia ja tulee Q. proliinia taas kertyy joten valiutuu W ja P eikä H ja E tai R., eli tulee polyglutamiineja, atrofiinia. Mitokondriaalinen sairaus ehkä, sillä proliinidehydrogenaasi on mitokondriaalinen. Jos nyt tuottuu liikaa PQ dipeptedejä, ei entsyymit riitä niiten peptidaaseiksi kehossa, mikä olisi sekundääristä. Ehkä., tai eri asia.

https://www.ncbi.nlm.nih.gov/gene/5625

Official Symbol: PRODHprovided by HGNC
Official Full Name: proline dehydrogenase 1provided by HGNC
Also known as: POX; PIG6; HSPOX2; PRODH1; PRODH2; TP53I6
Summary: This gene encodes a mitochondrial protein that catalyzes the first step in proline degradation. Mutations in this gene are associated with hyperprolinemia type 1 and susceptibility to schizophrenia 4 (SCZD4). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2010]
Expression Biased expression in small intestine (RPKM 24.9), skin (RPKM 13.7) and 11 other tissues See more Orthologs mouse all

GeneRIFs: Gene References Into Functions

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Preferred Names: proline dehydrogenase 1, mitochondrial

Names: p53-induced gene 6 protein; proline dehydrogenase (oxidase) 1; proline oxidase 2; proline oxidase, mitochondrial; tumor protein p53 inducible protein 6

Katson proliinidehydrogenaasiensyymiä ensin.

https://www.ncbi.nlm.nih.gov/protein/NP_057419.5

proline dehydrogenase 1, mitochondrial isoform 1 precursor [Homo sapiens]

NCBI Reference Sequence: NP_057419.5

Identical Proteins FASTA Graphics

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LOCUS       NP_057419                600 aa            linear   PRI 09-JUN-2019
DEFINITION  proline dehydrogenase 1, mitochondrial isoform 1 precursor [Homo
            sapiens].
ACCESSION   NP_057419 NP_005965
VERSION     NP_057419.5
DBSOURCE    REFSEQ: accession NM_016335.5
KEYWORDS    RefSeq; RefSeq Select.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (residues 1 to 600)
  AUTHORS   Moreira JBN, Wohlwend M, Fenk S, Amellem I, Flatberg A, Kraljevic
            J, Marinovic J, Ljubkovic M, Bjorkoy G and Wisloff U.
  TITLE     Exercise Reveals Proline Dehydrogenase as a Potential Target in
            Heart Failure
  JOURNAL   Prog Cardiovasc Dis 62 (2), 193-202 (2019)
   PUBMED   30867130
  REMARK    GeneRIF: Proline Dehydrogenase (PRODH) expression is reduced in
            human with Heart Failure. PRODH appears to be crucial to sustain
            normal mitochondrial function and maintenance of ATP levels in
            human cardiomyocytes in a hypoxic environment, as well as for redox
            homeostasis in both normoxic and hypoxic conditions.
            Review article
REFERENCE   2  (residues 1 to 600)
  AUTHORS   Olivares O, Mayers JR, Gouirand V, Torrence ME, Gicquel T, Borge L,
            Lac S, Roques J, Lavaut MN, Berthezene P, Rubis M, Secq V, Garcia
            S, Moutardier V, Lombardo D, Iovanna JL, Tomasini R, Guillaumond F,
            Vander Heiden MG and Vasseur S.
  TITLE     Collagen-derived proline promotes pancreatic ductal adenocarcinoma
            cell survival under nutrient limited conditions
  JOURNAL   Nat Commun 8, 16031 (2017)
   PUBMED   28685754
  REMARK    GeneRIF: PRODH1-mediated proline metabolism promotes pancreatic
            ductal adenocarcinoma growth.
            Publication Status: Online-Only
REFERENCE   3  (residues 1 to 600)
  AUTHORS   Nagano T, Nakashima A, Onishi K, Kawai K, Awai Y, Kinugasa M,
            Iwasaki T, Kikkawa U and Kamada S.
  TITLE     Proline dehydrogenase promotes senescence through the generation of
            reactive oxygen species
  JOURNAL   J. Cell. Sci. 130 (8), 1413-1420 (2017)
   PUBMED   28264926
  REMARK    GeneRIF: this study shows that PRODH plays a causative role in DNA
            damage-induced senescence through the enzymatic generation of
            reactive oxygen species
REFERENCE   4  (residues 1 to 600)
  AUTHORS   Zareba I, Surazynski A, Chrusciel M, Miltyk W, Doroszko M, Rahman N
            and Palka J.
  TITLE     Functional Consequences of Intracellular Proline Levels
            Manipulation Affecting PRODH/POX-Dependent Pro-Apoptotic Pathways
            in a Novel in Vitro Cell Culture Model
  JOURNAL   Cell. Physiol. Biochem. 43 (2), 670-684 (2017)
   PUBMED   28942439
  REMARK    GeneRIF: PRODH/POX knockdown decreased DNA and collagen
            biosynthesis, whereas increased prolidase activity and
            intracellular proline level in MCF-7shPRODH/POX cells.
REFERENCE   5  (residues 1 to 600)
  AUTHORS   Crabtree GW, Park AJ, Gordon JA and Gogos JA.
  TITLE     Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic
            Transmission through GAD Blockade
  JOURNAL   Cell Rep 17 (2), 570-582 (2016)
   PUBMED   27705802
  REMARK    GeneRIF: Here, we show that Prodh-deficient mice with elevated CNS
            L-proline display specific deficits in high-frequency GABA-ergic
            transmission and gamma-band oscillations. We find that L-proline is
            a GABA-mimetic and can act at multiple GABA-ergic targets
REFERENCE   6  (residues 1 to 600)
  AUTHORS   Adams MD, Kerlavage AR, Fleischmann RD, Fuldner RA, Bult CJ, Lee
            NH, Kirkness EF, Weinstock KG, Gocayne JD, White O et al.
  TITLE     Initial assessment of human gene diversity and expression patterns
            based upon 83 million nucleotides of cDNA sequence
  JOURNAL   Nature 377 (6547 Suppl), 3-174 (1995)
   PUBMED   7566098
REFERENCE   7  (residues 1 to 600)
  AUTHORS   Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R,
            Borrow J, Gos A, Nestadt G, Wolyniec PS, Lasseter VK et al.
  TITLE     Schizophrenia susceptibility associated with interstitial deletions
            of chromosome 22q11
  JOURNAL   Proc. Natl. Acad. Sci. U.S.A. 92 (17), 7612-7616 (1995)
   PUBMED   7644464
REFERENCE   8  (residues 1 to 600)
  AUTHORS   Lindsay,E.A., Morris,M.A., Gos,A., Nestadt,G., Wolyniec,P.S.,
            Lasseter,V.K., Shprintzen,R., Antonarakis,S.E., Baldini,A. and
            Pulver,A.E.
  TITLE     Schizophrenia and chromosomal deletions within 22q11.2
  JOURNAL   Am. J. Hum. Genet. 56 (6), 1502-1503 (1995)
   PUBMED   7762575
REFERENCE   9  (residues 1 to 600)
  AUTHORS   Coon H, Jensen S, Holik J, Hoff M, Myles-Worsley M, Reimherr F,
            Wender P, Waldo M, Freedman R, Leppert M et al.
  TITLE     Genomic scan for genes predisposing to schizophrenia
  JOURNAL   Am. J. Med. Genet. 54 (1), 59-71 (1994)
   PUBMED   7909992
REFERENCE   10 (residues 1 to 600)
  AUTHORS   Scambler PJ, Kelly D, Lindsay E, Williamson R, Goldberg R,
            Shprintzen R, Wilson DI, Goodship JA, Cross IE and Burn J.
  TITLE     Velo-cardio-facial syndrome associated with chromosome 22 deletions
            encompassing the DiGeorge locus
  JOURNAL   Lancet 339 (8802), 1138-1139 (1992)
   PUBMED   1349369
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from AC007326.28.
            On Jan 31, 2019 this sequence version replaced NP_057419.4.
            
            Summary: This gene encodes a mitochondrial protein that catalyzes
            the first step in proline degradation. Mutations in this gene are
            associated with hyperprolinemia type 1 and susceptibility to
            schizophrenia 4 (SCZD4). This gene is located on chromosome
            22q11.21, a region which has also been associated with the
            contiguous gene deletion syndromes, DiGeorge and CATCH22.
            Alternatively spliced transcript variants encoding different
            isoforms have been found for this gene. [provided by RefSeq, Aug
            2010].
            
            Transcript Variant: This variant (1) encodes the longer isoform
            (1).
            
            Sequence Note: The RefSeq transcript and protein were derived from
            genomic sequence to make the sequence consistent with the reference
            genome assembly. The genomic coordinates used for the transcript
            record were based on alignments.
            
            Publication Note:  This RefSeq record includes a subset of the
            publications that are available for this gene. Please see the Gene
            record to access additional publications.
            
            ##Evidence-Data-START##
            CDS exon combination :: SRR1803614.19175.1, SRR1660805.167443.1
                                    [ECO:0000331]
            RNAseq introns       :: mixed/partial sample support SAMEA1965299,
                                    SAMEA1966682 [ECO:0000350]
            ##Evidence-Data-END##
            
            ##RefSeq-Attributes-START##
            gene product(s) localized to mito. :: reported by MitoCarta
            RefSeq Select criteria             :: based on conservation,
                                                  expression, longest protein
            ##RefSeq-Attributes-END##
FEATURES             Location/Qualifiers
     source          1..600
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="22"
                     /map="22q11.21"
     Protein         1..600
                     /product="proline dehydrogenase 1, mitochondrial isoform 1
                     precursor"
                     /EC_number="1.5.5.2"
                     /note="tumor protein p53 inducible protein 6; proline
                     oxidase, mitochondrial; proline dehydrogenase 1,
                     mitochondrial; proline oxidase 2; proline dehydrogenase
                     (oxidase) 1; p53-induced gene 6 protein"
                     /calculated_mol_wt=67898
     Site            368
                     /site_type="acetylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="N6-acetyllysine. {ECO:0000250|UniProtKB:Q9WU79};
                     propagated from UniProtKB/Swiss-Prot (O43272.3)"
     Site            486
                     /site_type="acetylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="N6-acetyllysine. {ECO:0000250|UniProtKB:Q9WU79};
                     propagated from UniProtKB/Swiss-Prot (O43272.3)"
     CDS             1..600
                     /gene="PRODH"
                     /gene_synonym="HSPOX2; PIG6; POX; PRODH1; PRODH2; TP53I6"
                     /coded_by="NM_016335.5:205..2007"
                     /note="isoform 1 precursor is encoded by transcript
                     variant 1"
                     /db_xref="CCDS:CCDS13754.1"
                     /db_xref="GeneID:5625"
                     /db_xref="HGNC:HGNC:9453"
                     /db_xref="MIM:606810"
ORIGIN      
        1 malrralpal rpciprfvpl stapasreqp aagpaavpgg gsatavrppv pavdfgnaqe
       61 ayrsrrtwel arsllvlrlc awpallarhe qllyvsrkll gqrlfnklmk mtfyghfvag
      121 edqesiqpll rhyrafgvsa ildygveedl speeaehkem esctsaaerd gsgtnkrdkq
      181 yqahwafgdr rngvisarty fyaneakcds hmetflrcie asgrvsddgf iaikltalgr
      241 pqfllqfsev lakwrcffhq maveqgqagl aamdtkleva vlqesvaklg iasraeiedw
      301 ftaetlgvsg tmdlldwssl idsrtklskh lvvpnaqtgq lepllsrfte eeelqmtrml
      361 qrmdvlakka temgvrlmvd aeqtyfqpai srltlemqrk fnvekplifn tyqcylkday
      421 dnvtldvela rregwcfgak lvrgaylaqe raraaeigye dpinptyeat namyhrcldy
      481 vleelkhnak akvmvashne dtvrfalrrm eelglhpadh rvyfgqllgm cdqisfplgq
      541 agypvykyvp ygpvmevlpy lsrralenss lmkgthrerq llwlellrrl rtgnlfhrpa
//

PolyQ Ataxin-2 , ATXN2 (12q24.12)

https://www.ncbi.nlm.nih.gov/pubmed/27103069/

ATXN2provided by HGNC
Official Full Name: ataxin 2provided by HGNC
Also known as: ATX2; SCA2; TNRC13
Summary: This gene belongs to a group of genes that is associated with microsatellite-expansion diseases, a class of neurological and neuromuscular disorders caused by expansion of short stretches of repetitive DNA. The protein encoded by this gene has two globular domains near the N-terminus, one of which contains a clathrin-mediated trans-Golgi signal and an endoplasmic reticulum (ER) exit signal. The encoded cytoplasmic protein localizes to the endoplasmic reticulum (ER) and plasma membrane (PM), is involved in endocytosis, and modulates mTOR signals, modifying ribosomal translation and mitochondrial function. The N-terminal region of the protein contains a polyglutamine (polyQ) tract of 14-31 residues that can be expanded in the pathogenic state to 32-200 residues. Intermediate length expansions of this tract increase susceptibility to amyotrophic lateral sclerosis, while long expansions of this tract result in spinocerebellar ataxia-2, an autosomal-dominantly inherited, neurodegenerative disorder. Genome-wide association studies indicate that loss-of-function mutations in this gene may be associated with susceptibility to type I diabetes, obesity and hypertension. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]
Expression: Ubiquitous expression in testis (RPKM 11.3), brain (RPKM 9.4) and 25 other tissues See more
Orthologs

Preferred Names: ataxin-2

Names: spinocerebellar ataxia type 2 protein; trinucleotide repeat-containing gene 13 protein

https://www.ncbi.nlm.nih.gov/protein/NP_001297052.1

ORIGIN      
        1 mrmvhiltsv vcdlvldaah ekstesssgp kreeimesil fkcsdfvvvq fkdmdssyak
       61 rdaftdsais akvngehkek dlepwdagel taneeleale ndvsngwdpn dmfryneeny
      121 gvvstydssl ssytvplerd nseeflkrea ranqlaeeie ssaqykarva lenddrseee
      181 kytavqrnss ereghsintr enkyippgqr nreviswgsg rqnsprmgqp gsgsmpsrst
      241 shtsdfnpns gsdqrvvngg vpwpspcpsp ssrppsryqs gpnslppraa tptrppsrpp
      301 srpsrppshp sahgspapvs tmpkrmsseg pprmspkaqr hprnhrvsag rgsissglef
      361 vshnppseaa tppvartsps ggtwssvvsg vprlspkthr prsprqnsig ntpsgpvlas
      421 pqagiiptea vampipaasp tpaspasnra vtpsseakds rlqdqrqnsp agnkenikpn
      481 etspsfskae nkgispvvse hrkqiddlkk fkndfrlqps stsesmdqll nknregeksr
      541 dlikdkieps akdsfienss snctsgsskp nspsispsil sntehkrgpe vtsqgvqtss
      601 packqekddk eekkdaaeqv rkstlnpnak efnprsfsqp kpsttptspr pqaqpspsmv
      661 ghqqptpvyt qpvcfapnmm ypvpvspgvq plypipmtpm pvnqaktyra vpnmpqqrqd
      721 qhhqsammhp asaagppiaa tppaystqyv ayspqqfpnq plvqhvphyq sqhphvyspv
      781 iqgnarmmap pthaqpglvs ssatqygahe qthamyvstg slaqqyahpn atlhphtphp
      841 qpsatptgqq qsqhggshpa pspvqhhqhq aaqalhlasp qqqsaiyhag laptppsmtp
      901 asntqspqns fpaaqqtvft ihpshvqpay tnpphmahvp qahvqsgmvp shptahapmm
      961 lmttqppggp qaalaqsalq pipvsttahf pymthpsvqa hhqqql

Conserved Domains (4) summary

pfam06741 Location:144 → 205: LsmAD; LsmAD domain

pfam14438 Location:3 → 76: SM-ATX; Ataxin 2 SM domain

cl26386 Location:303 → 494: DNA_pol3_gamma3; DNA polymerase III subunits gamma and tau domain III

cl26464 Location:664 → 988

Atrophin-1 family

Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteristic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

cl26464 Atrophin-1 Superfamily (this model, PSSM-Id:331285 is obsolete)

GeneRIFs: Gene References Into Functions

Submit: New GeneRIF Correction See all GeneRIFs (108)

torsdag 20 juni 2019

C9ORF72 (9p21.2), SMRC8 (17p11.2) ja WDR41 (5q13.3-q14.1) lysosomaalista yhteistyötä aivojen joustavan reletoiminnan taustalla

https://www.ncbi.nlm.nih.gov/gene/203228

Official Symbol: C9orf72
Official Full Name: C9orf72-SMCR8 complex subunit
Also known as: ALSFTD; DENND9; FTDALS; DENNL72; FTDALS1
Summary: The protein encoded by this gene plays an important role in the regulation of endosomal trafficking, and has been shown to interact with Rab proteins that are involved in autophagy and endocytic transport. Expansion of a GGGGCC nucleoide repeat from 2-22 copies to 700-1600 copies in the intronic sequence between alternate 5' exons in transcripts from this gene is associated with 9p-linked ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) (PMID: 21944778, 21944779).; Studies suggest that hexanucleotide expansions could result in the selective stabilization of repeat-containing pre-mRNA, and the accumulation of insoluble dipeptide (WD containing) repeat protein aggregates that could be pathogenic in FTD-ALS patients (PMID: 23393093). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2016]
Expression Ubiquitous expression in appendix (RPKM 9.7), testis (RPKM 9.3) and 25 other tissues See more Orthologs mouse all

Preferred Names: guanine nucleotide exchange C9orf72

Names: protein C9orf72

https://www.ncbi.nlm.nih.gov/protein/NP_001242983.1

The G-rich Repeats in FMR1 and C9orf72 Loci Are Hotspots for Local
            Unpairing of DNA.

The C9orf72 GGGGCC repeat is translated into aggregating
            dipeptide-repeat proteins in FTLD/ALS

ORIGIN      
        1 mstlcpppsp avakteials gkspllaatf aywdnilgpr vrhiwapkte qvllsdgeit
       61 flanhtlnge ilrnaesgai dvkffvlsek gviivslifd gnwngdrsty glsiilpqte
      121 lsfylplhrv cvdrlthiir kgriwmhker qenvqkiile gtermedqgq siipmltgev
      181 ipvmellssm kshsvpeeid iadtvlnddd igdschegfl lnaisshlqt cgcsvvvgss
      241 aekvnkivrt lclfltpaer kcsrlceaes sfkyesglfv qgllkdstgs fvlpfrqvmy
      301 apyptthidv dvntvkqmpp chehiynqrr ymrseltafw ratseedmaq dtiiytdesf
      361 tpdlnifqdv lhrdtlvkaf ldqvfqlkpg lslrstflaq fllvlhrkal tlikyieddt
      421 qkgkkpfksl rnlkidldlt aegdlniima laekikpglh sfifgrpfyt svqerdvlmt
      481 f
//

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202986/figure/F4/

Conserved Domains (1) summary

pfam15019 Location:61 → 324

C9orf72-like; C9orf72-like protein family

The precise function of this family is unknown but members have been found to be localized in the cytoplasm of brain tissue. Defects in the gene, C9orf72, are the cause of frontotemporal dementia and/or amyotrophic lateral sclerosis (FTDALS) which is an autosomal dominant neurodegenerative disorder. The disorder is caused by a large expansion of a GGGGCC hexa-nucleotide within the first C9orf72 intron located between the first and the second non-coding exons. The expansion leads to the loss of transcription of one of the two transcripts encoding isoform 1 and to the formation of nuclear RNA foci. This domain family is found in eukaryotes, and is typically between 230 and 250 amino acids in length. There is a single completely conserved residue F that may be functionally important.

Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.Neuron 2011 Oct 20; 72(2):245-56

Related articles in PubMed

Discovery of Novel DENN Proteins: Implications for the Evolution of Eukaryotic Intracellular Membrane Structures and Human Disease. Zhang D, et al. Front Genet, 2012. PMID 23248642, Free PMC ArticleThe tripartite DENN module, comprised of a N-terminal longin domain, followed by DENN, and d-DENN domains, is a GDP-GTP exchange factor (GEFs) for Rab GTPases, which are regulators of practically all membrane trafficking events in eukaryotes. Using sequence and structure analysis we identify multiple novel homologs of the DENN module, many of which can be traced back to the ancestral eukaryote. These findings provide unexpected leads regarding key cellular processes such as autophagy, vesicle-vacuole interactions, chromosome segregation, and human disease. Of these, SMCR8, the folliculin interacting protein-1 and 2 (FNIP1 and FNIP2), nitrogen permease regulator 2 (NPR2), and NPR3 are proposed to function in recruiting Rab GTPases during different steps of autophagy, fusion of autophagosomes with the vacuole and regulation of cellular metabolism. Another novel DENN protein identified in this study is C9ORF72; expansions of the hexanucleotide GGGGCC in its first intron have been recently implicated in amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). While this mutation is proposed to cause a RNA-level defect, the identification of C9ORF72 as a potential DENN-type GEF raises the possibility that at least part of the pathology might relate to a specific Rab-dependent vesicular trafficking process, as has been observed in the case of some other neurological conditions with similar phenotypes. We present evidence that the longin domain, such as those found in the DENN module, are likely to have been ultimately derived from the related domains found in prokaryotic GTPase-activating proteins of MglA-like GTPases. Thus, the origin of the longin domains from this ancient GTPase-interacting domain, concomitant with the radiation of GTPases, especially of the Rab clade, played an important role in the dynamics of eukaryotic intracellular membrane systems.
C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling. Amick J, et al. Mol Biol Cell, 2016 Oct 15. PMID 27559131, Free PMC Article Hexanucleotide expansion in an intron of the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia. However, beyond bioinformatics predictions that suggested structural similarity to folliculin, the Birt-Hogg-Dubé syndrome tumor suppressor, little is known about the normal functions of the C9orf72 protein. To address this problem, we used genome-editing strategies to investigate C9orf72 interactions, subcellular localization, and knockout (KO) phenotypes. We found that C9orf72 robustly interacts with SMCR8 (a protein of previously unknown function). We also observed that C9orf72 localizes to lysosomes and that such localization is negatively regulated by amino acid availability. Analysis of C9orf72 KO, SMCR8 KO, and double-KO cell lines revealed phenotypes that are consistent with a function for C9orf72 at lysosomes. These include abnormally swollen lysosomes in the absence of C9orf72 and impaired responses of mTORC1 signaling to changes in amino acid availability (a lysosome-dependent process) after depletion of either C9orf72 or SMCR8. Collectively these results identify strong physical and functional interactions between C9orf72 and SMCR8 and support a lysosomal site of action for this protein complex.
The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis. Zhang Y, et al. Genes Dev, 2018 Jul 1. PMID 29950492, While a mutation in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS), much remains to be learned concerning the function of the protein normally encoded at this locus. To elaborate further on functions for C9ORF72, we used quantitative mass spectrometry-based proteomics to identify interacting proteins in motor neurons and found that its long isoform complexes with and stabilizes SMCR8, which further enables interaction with WDR41. To study the organismal and cellular functions for this tripartite complex, we generated Smcr8 loss-of-function mutant mice and found that they developed phenotypes also observed in C9orf72 loss-of-function animals, including autoimmunity. Along with a loss of tolerance for many nervous system autoantigens, we found increased lysosomal exocytosis in Smcr8 mutant macrophages. In addition to elevated surface Lamp1 (lysosome-associated membrane protein 1) expression, we also observed enhanced secretion of lysosomal components-phenotypes that we subsequently observed in C9orf72 loss-of-function macrophages. Overall, our findings demonstrate that C9ORF72 and SMCR8 have interdependent functions in suppressing autoimmunity as well as negatively regulating lysosomal exocytosis-processes of potential importance to ALS.
Multiplex image-based autophagy RNAi screening identifies SMCR8 as ULK1 kinase (unc-51 like autophagy activating kinase 1) activity and gene expression regulator. Jung J, et al. Elife, 2017 Feb 14. PMID 28195531, Free PMC Article
The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway. Sullivan PM, et al. Acta Neuropathol Commun, 2016 May 18. PMID 27193190,* Free PMC Article .. Here we report the identification of two binding partners of C9orf72: SMCR8 and WDR41. We show that WDR41 interacts with the C9orf72/SMCR8 heterodimer and WDR41 is tightly associated with the Golgi complex. We further demonstrate that C9orf72/SMCR8/WDR41 associates with the FIP200/Ulk1 complex, which is essential for autophagy initiation (OBS.* FREE ARTICLE highlights well!)

See all (22) citations in PubMed

GeneRIFs: Gene References Into Functions

*The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway.

Sullivan PM¹, Zhou X¹, Robins AM¹, Paushter DH¹, Kim D¹, Smolka MB¹, Hu F². Abstract

Hexanucleotide repeat expansion in the C9orf72 gene is a leading cause of frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS). Reduced expression of C9orf72 has been proposed as a possible disease mechanism. However, the cellular function of C9orf72 remains to be characterized. Here we report the identification of two binding partners of C9orf72: SMCR8 and WDR41. We show that WDR41 interacts with the C9orf72/SMCR8 heterodimer and WDR41 is tightly associated with the Golgi complex. We further demonstrate that C9orf72/SMCR8/WDR41 associates with the FIP200/Ulk1 complex, which is essential for autophagy initiation. C9orf72 deficient mice, generated using the CRISPR/Cas9 system, show severe inflammation in multiple organs, including lymph node, spleen and liver. Lymph node enlargement and severe splenomegaly are accompanied with macrophage infiltration. Increased levels of autophagy and lysosomal proteins and autophagy defects were detected in both the spleen and liver of C9orf72 deficient mice, supporting an in vivo role of C9orf72 in regulating the autophagy/lysosome pathway. In summary, our study elucidates potential physiological functions of C9orf72 and disease mechanisms of ALS/FTLD. KEYWORDS:

Amyotrophic lateral sclerosis; Autophagy; C9orf72; FIP200/RB1CC1; Frontotemporal lobar degeneration; Lysosome; SMCR8; Ulk1; WDR41

(KUVASSA näkyy tripartiitti kompleksi: C9ORFt2-SMCR8-WDR41):

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WDR41 (5q13.3-14.1), WD repeat domain 41, MISTP048
https://www.ncbi.nlm.nih.gov/gene/55255

Official Full Name WD repeat domain 41provided by HGNC
Gene type protein coding
Also known as MSTP048
ExpressionUbiquitous expression in thyroid (RPKM 15.6), brain (RPKM 8.1) and 25 other tissues See more Orthologs mouse all


(Tässä on linkki jonka avulla pystyy tarkkailemaan kaikki wd- domaanit alla olevasta proteiinista.)
https://www.ncbi.nlm.nih.gov/protein/NP_060738.2

ORIGIN      
        1 mlrwligggr epqglaeksp lqtigeeqtq npytellvlk ahhdivrflv qlddyrfasa
       61 gddgivvvwn aqtgekllel nghtqkitai itfpslesce eknqliltas adrtvivwdg
      121 dttrqvqris cfqstvkclt vlqrldvwls ggndlcvwnr kldllcktsh lsdtgisalv
      181 eipkncvvaa vgkeliifrl vaptegslew dilevkrlld hqdnilslin vndlsfvtgs
      241 hvgeliiwda ldwtmqayer nfwdpspqld tqqeiklcqk sndisihhft cdeenvfaav
      301 grglyvyslq mkrviacqkt ahdsnvlhva rlpnrqlisc sedgsvriwe lrekqqlaae
      361 pvptgffnmw gfgrvskqas qpvkkqqena tscsleligd lighsssvem flyfedhglv
      421 tcsadhliil wkngeresgl rslrlfqkle engdlylav
//

Conserved Domains (2) summary

sd00039 Location:88 → 131: 7WD40; WD40 repeat [structural motif]; WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

cl25539 Location:38 → 350: WD40; WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from ..

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The Proline Cycle As a Potential Cancer Therapy Target.

Abstract

P5CS, D1-pyrroline-5-carboxylate synthetase ALDH18A1 (10q24.19

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Conserved Domains (4) summary

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torsdag 20 juni 2019

C9ORF72 (9p21.2), SMRC8 (17p11.2) ja WDR41 (5q13.3-q14.1) lysosomaalista yhteistyötä aivojen joustavan reletoiminnan taustalla

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