KBTBD3 /BKLHD3

Tutkimusten alainen Kelch-superperheen  KBTBD-ryhmän  proteiini , jota  ilmentyy eniten aivoissa, siten kilpirauhasessa ja useissa muissa kudoksissa . https://genecards.weizmann.ac.il/v3/cgi-bin/carddisp.pl?gene=KBTBD3: Funktio pohdittavana.
https://genecards.weizmann.ac.il/v3/cgi-bin/carddisp.pl?gene=KBTBD3

HGNC Gene Families:

BTBD: BTB/POZ domain containing Selected InterPro protein domains (see all 7):  IPR017096 Kelch-like_gigaxonin-typ  IPR000210 BTB/POZ-like  IPR006652 Kelch_1  IPR011333 BTB/POZ_fold  IPR013069 BTB_POZ Graphical View of Domain Structure for InterPro Entry Q8NAB2 ProtoNet protein and cluster: Q8NAB2 2 Blocks protein domains: IPB000210 BTB/POZ domain IPB011705 BTB/Kelch-associated UniProtKB/Swiss-Prot: KBTB3_HUMAN, Q8NAB2 Similarity: Contains 1 BACK (BTB/Kelch associated) domain Similarity: Contains 1 BTB (POZ) domain Similarity: Contains 5 Kelch repeats

Koetan hahmottaa rakennetta ja verrata esim  gigaxoniin, onko jotain tai mitään  samaa sekvenssipätkää) Kesken...Minkälainen Znf?


 KBTBD3,https://www.ncbi.nlm.nih.gov/gene/143879

Also known as

BKLHD3

Expression

Ubiquitous expression in brain (RPKM 1.9), thyroid (RPKM 1.3) and 25 other tissues See more

Orthologs

mouse all

       ##Evidence-Data-END##
FEATURES             Location/Qualifiers
     source          1..533
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="11"
                     /map="11q22.3"
     Protein         1..533
                     /product="kelch repeat and BTB domain-containing protein 3
                     isoform 2"
                     /note="BTB and kelch domain containing 3; kelch repeat and
                     BTB domain-containing protein 3; BTB and kelch
                     domain-containing protein 3; kelch repeat and BTB (POZ)
                     domain containing 3; epididymis secretory sperm binding
                     protein"
                     /calculated_mol_wt=60545
     Region          16..507
                     /region_name="BTB"
                     /note="Broad-Complex, Tramtrack and Bric a brac; cl28614"
                     /db_xref="CDD:333434"
     Region          255..310
                     /region_name="KELCH repeat"
                     /note="KELCH repeat [structural motif]"
                     /db_xref="CDD:276965"
     Region          314..362
                     /region_name="KELCH repeat"
                     /note="KELCH repeat [structural motif]"
                     /db_xref="CDD:276965"
     Region          365..410
                     /region_name="KELCH repeat"
                     /note="KELCH repeat [structural motif]"
                     /db_xref="CDD:276965"
     Region          462..507
                     /region_name="KELCH repeat"
                     /note="KELCH repeat [structural motif]"
                     /db_xref="CDD:276965"
     CDS             1..533
                     /gene="KBTBD3"
                     /gene_synonym="BKLHD3"
                     /coded_by="NM_001330359.1:633..2234"
                     /note="isoform 2 is encoded by transcript variant 3"
                     /db_xref="CCDS:CCDS81621.1"
                     /db_xref="GeneID:143879"
                     /db_xref="HGNC:HGNC:22934"
ORIGIN      
        1 mfevnmkerd dgsvtitnls skavkafldy aytgktkitd dnvemffqls sflqvsflsk
       61 acsdfliksi nlvnclqlls isdsygstsl fdhalhfvqh hfsllfkssd flemnfgvlq
      121 kclesdelnv peeemvlkvv lswtkhnles rqkylphlie kvrlhqlsee tlqdclfnee
      181 sllkstncfd iimdaikcvq gsgglfpdar psttekyifi hkteengenq ytfcyniksd
      241 swkilpqshl idlpgsslss ygekifltgg ckgkccrtvr lhiaesyhda tdqtwcycpv
      301 kndfflvstm ktprtmhtsv maldrlfvig gktrgsrdik slldvesynp lskewisvsp
      361 lprgiyypea stcqnviyvl gseveitdaf npsldcffky nattdqwsel vaefgqffha
      421 tlikavpvnc tlyicdlsty kvysfcpdtc vwkgegsfec agfnagaigi edkiyilggd
      481 yapdeitdev qvyhsnrsew eevspmpral tefycqviqf nkyrdpwfsn lca
//

https://www.ncbi.nlm.nih.gov/pubmed/?term=KBTBD3

VERTAA GIGAXONIINI sekvenssiin,  KLHL16:

ORIGIN      
        1 maegsavsdp qhaarllral ssfreesrfc dahlvldgee ipvqknilaa aspyirtkln
       61 ynppkddgst ykielegisv mvmreildyi fsgqirlned tiqdvvqaad lllltdlktl
      121 cceflegcia aencigirdf alhyclhhvh ylateyleth frdvssteef lelspqklke
      181 visleklnvg neryvfeavi rwiahdteir kvhmkdvmsa lwvsgldssy lreqmlnepl
      241 vreivkecsn iplsqpqqge amlanfkprg ysecivtvgg eervsrkpta amrcmcplyd
      301 pnrqlwiela plsmprinhg vlsaegflfv fggqdenkqt lssgekydpd antwtalppm
      361 nearhnfgiv eidgmlyilg gedgekelis mecydiyskt wtkqpdltmv rkigcyaamk
      421 kkiyamgggs ygklfesvec ydprtqqwta icplkerrfg avacgvamel yvfggvrsre
      481 daqgsemvtc ksefyhdefk rwiylndqnl cipasssfvy gavpigasiy vigdldtgtn
      541 ydyvrefkrs tgtwhhtkpl lpsdlrrtgc aalrianckl frlqlqqglf rirvhsp
//

ACLY entsyymi kolinergisessä neuronissa ym. (2019)

https://www.ncbi.nlm.nih.gov/pubmed/30944476

Nature. 2019 Apr;568(7753):571-575. doi: 10.1038/s41586-019-1095-5. Epub 2019 Apr 3.

Structure of ATP citrate lyase (ACLY)  and the origin of citrate synthase(CS)  in the Krebs cycle.

Verschueren KHG^1,2, Blanchet C³, Felix J⁴, Dansercoer A^1,2, De Vos D⁵, Bloch Y^1,2, Van Beeumen J⁶, Svergun D³, Gutsche I⁴, Savvides SN^1,2, Verstraete K^7,8.

1Unit for Structural Biology, VIB Center for Inflammation Research, Ghent, Belgium.

2Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.3European Molecular Biology Laboratory (EMBL), Hamburg Outstation c/o DESY, Hamburg, Germany.4University of Grenoble Alpes, CNRS, CEA, CNRS, IBS, Grenoble, France.5Integrated Molecular Plant Physiology Research, Department of Biology, University of Antwerp, Antwerp, Belgium.6Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.7Unit for Structural Biology, VIB Center for Inflammation Research, Ghent, Belgium. kenneth.verstraete@ugent.be.8Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium. kenneth.verstraete@ugent.be.

Abstract

Across different kingdoms of life, ATP citrate lyase (ACLY, also known as ACL) catalyses the ATP-dependent and coenzyme A (CoA)-dependent conversion of citrate, a metabolic product of the Krebs cycle, to oxaloacetate and the high-energy biosynthetic precursor acetyl-CoA¹. The latter fuels pivotal biochemical reactions such as the synthesis of fatty acids, cholesterol and acetylcholine², and the acetylation of histones and proteins^3,4. In autotrophic prokaryotes, ACLY is a hallmark enzyme of the reverse Krebs cycle (also known as the reductive tricarboxylic acid cycle), which fixates two molecules of carbon dioxide in acetyl-CoA^5,6. In humans, ACLY links carbohydrate and lipid metabolism and is strongly expressed in liver and adipose tissue¹ and in cholinergic neurons^2,7.

 The structural basis of the function of ACLY remains unknown. Here we report high-resolution crystal structures of bacterial, archaeal and human ACLY, and use distinct substrate-bound states to link the conformational plasticity of ACLY to its multistep catalytic itinerary. Such detailed insights will provide the framework for targeting human ACLY in cancer^8,9,10,11 and hyperlipidaemia^12,13. Our structural studies also unmask a fundamental evolutionary relationship that links citrate synthase, the first enzyme of the oxidative Krebs cycle, to an ancestral tetrameric citryl-CoA lyase module that operates in the reverse Krebs cycle. This molecular transition marked a key step in the evolution of metabolism on Earth.

KLHL25(ENC-2) ja ATP:sitraattilyaasi ACLY

 Kelch- superperheen proteiini KLHL25 toimii adaptorina kun CUL3  johtaa ATP:sitraattilyaasia proteosomisilppuriin. 

Entä miten nämä toimivat aivossa?
Aivossa tarvitaan  jatkuvaa rasva-aine ja kolesterolisynteesiä, koska aivo on  rasvamoduli, koostunut hyvin monimutkaisista j monipuolisista lipidiaineista.  Lisäksi neuronit tarvitsevat AcetylCoaa  muodostamaan hermonvälittäjäainetta asetylkoliinia kolinergisessä järjestelmässä. Se toimii eräänlaisena clearing-tekijänä   hermoissa ja  varsinkin tahdonalaisessa ajattelussa ja toiminnassa se on tärkeä.   hermorata. Löytyykö jotain konkreettista karttaa  sitraatista, kelch-proteiinifunktiosta,  ja yhteydestä muihin  elementaarisiin etikkahapon ja sitruunahapon tasoa kuvaaviin kaavoihin?


Cullin3–KLHL25 ubiquitin ligase targetsACLY for degradation to inhibit lipidsynthesis and tumor progression

 Cen Zhang,1,4Juan Liu,1,4Grace Huang,2Yuhan Zhao,1Xuetian Yue,1Hao Wu,1Jun Li,1Junlan Zhu,2Zhiyuan Shen,1Bruce G. Haffty,1Wenwei Hu,1and Zhaohui Feng1,31Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State Universityof New Jersey, New Brunswick, New Jersey 08903, USA;2Nelson Institute of Environmental Medicine, New York UniversitySchool of Medicine, New York University, Tuxedo, New Jersey 10987, USA;3Department of Pharmacology, Rutgers University,The State University of New Jersey, Piscataway, New Jersey 08854, USA

 Increased lipid synthesis is a key characteristic of many cancers that is critical for cancer progression. ATP-citratelyase (ACLY), a key enzyme for lipid synthesis, is frequently overexpressed or activated in cancer to promote lipidsynthesis and tumor progression. Cullin3 (CUL3), a core protein for the CUL3–RING ubiquitin ligase complex, has been reported to be a tumor suppressor and frequently down-regulated in lung cancer. Here, we found that CUL3interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate anddegrade ACLY in cells. Through negative regulation of ACLY, CUL3 inhibits lipid synthesis, cell proliferation,and xenograft tumor growth of lung cancer cells. Furthermore, ACLY inhibitor SB-204990 greatly abolishes thepromoting effect of CUL3 down-regulation on lipid synthesis, cell proliferation, and tumor growth. Importantly, lowCUL3 expression is associated with high ACLY expression and poor prognosis in human lung cancer. In summary,our results identify CUL3–KLHL25 ubiquitin ligase as a novel negative regulator for ACLY and lipid synthesis anddemonstrate that decreased CUL3 expression is an important mechanism for increased ACLY expression and lipidsynthesis in lung cancer. These results also reveal that negative regulation of ACLY and lipid synthesis is a novel andcritical mechanism for CUL3 in tumor suppression.[Keywords: CUL3; ACLY; KLHL25; ubiquitination; lipid synthesis; tumor 

 


https://www.ncbi.nlm.nih.gov/pubmed/28161643

SIRT3 have been found to be neuroprotective in many neurological diseases, but its detail mechanism is only partially understood. In this study, MPP⁺ was used to treat SH-SY5Y cells as the cellular model of PD to test the role of SIRT3 and the mechanism may be involved in. We focused on the changes and relationship between SIRT3 and the key mitochondrial enzymes citrate synthase (CS) and isocitrate dehydrogenase 2 (IDH2). We found MPP⁺ decreased SIRT3 expression. And our results showed that the enzymatic activities of CS and IDH2 were significantly reduced in MPP⁺ treatment cells, while protein acetylation of CS and IDH2 increased. However overexpressed-SIRT3 partially reversed at least, the decline of CS activity and the increase of CS protein acetylation. IDH2 did not showed the same changes. The study suggested that SIRT3 deacetylated and activated CS activity. Hence, we conclude that SIRT3 exhibits neuroprotection via deacetylating and increasing mitochondrial enzyme activities.

Copyright © 2017 Elsevier Inc. All rights reserved.

Deacetylation; Enzyme activity; Mitochondria; Neuroprotection; Parkinson disease; SIRT3

https://i.pinimg.com/originals/b0/bd/44/b0bd4471753eb332a4d601c7e065ee6e.jpg 

 

ENC-1 (KLHL37) (5q13.3) Tumamatrixproteiini aivoissa, rajoittaa NRF2:n translatoitumista.

https://www.ncbi.nlm.nih.gov/gene/8507

Also known as

NRPB; CCL28; ENC-1; PIG10; KLHL35; KLHL37; TP53I10

Summary

This gene encodes a member of the kelch-related family of actin-binding proteins. The encoded protein plays a role in the oxidative stress response as a regulator of the transcription factor Nrf2, and expression of this gene may play a role in malignant transformation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]

Expression

Biased expression in brain (RPKM 180.1), gall bladder (RPKM 11.8) and 4 other tissues See more

Orthologs

General protein information

Preferred Names

ectoderm-neural cortex protein 1

Names

ectodermal-neural cortex 1 (with BTB domain)

ectodermal-neural cortex 1 (with BTB-like domain)

kelch-like 35

kelch-like family member 37

kelch-like protein 37

nuclear matrix protein NRP/B

nuclear restricted protein, BTB domain-like (brain)

p53-induced gene 10 protein

tumor protein p53 inducible protein 10

1. NM_001256576.1 → NP_001243505.1  ectoderm-neural cortex protein 1 isoform 2
   
   Status: REVIEWED

   ORIGIN      
           1 mfsgglkesq dsevnfdnsi hpevlellld yayssrviin eenaesllea gdmlefqdir
          61 dacaeflekn lhptnclgml llsdahqctk lyelswrmcl snfqtirkne dflqlpqdmv
         121 vqllsseele tederlvyes ainwisydlk krycylpell qtvrlallpa iylmenvame
         181 elitkqrksk eiveeairck lkilqndgvv tslcarprkt ghalfllggq tfmcdklylv
         241 dqkakeiipk adipsprkef sacaigckvy itggrgseng vskdvwvydt lheewskaap
         301 mlvarfghgs aelkhclyvv gghtaatgcl paspsvslkq vehydptink wtmvaplreg
         361 vsnaavvsak lklfafggts vshdklpkvq cydqcenrwt vpatcpqpwr ytaaavlgnq
         421 ifimggdtef sacsaykfns etyqwtkvgd vtakrmscha vasgnklyvv ggyfgiqrck
         481 tldcydptld vwnsittvpy sliptafvst wkhlps
   //

   
   

   Description

   Transcript Variant: This variant (4) uses an alternate splice site, lacks a portion of the 5' coding region and initiates translation at a downstream, in-frame start codon, compared to variant 1. The encoded isoform (2) has a shorter N-terminus, compared to isoform 1.

   Conserved Domains (5) summary

   smart00612
   Location:316 → 368

   Kelch; Kelch domain

   sd00038
   Location:257 → 301

   Kelch; KELCH repeat [structural motif]

   pfam00651
   Location:1 → 67

   BTB; BTB/POZ domain

   pfam01344
   Location:256 → 301

   Kelch_1; Kelch motif

   pfam07707
   Location:76 → 178

   BACK; BTB And C-terminal Kelch

(Huom:  Mayvenin sukuisen  KLHL1- geenin löytöä koskevan artikkelin yhteydssä oli maininta: "We have previously identified and characterized two actinbinding proteins, termed NRP/B/ENC-1 ( = KLHL37 tai KLHL35 ovat aiempia nimiä)  (16-18) and Mayven( (=KLHL2)  (19), predominantly expressed in brain. Tässä yhteydessä otan esiin tuon ENC-1 , jolla näyttä olleen kaksi KLHL  numeroa 37 ja 35 jossain vaiheessa tieteellisiä luokituksia). 

Tällä proteiinilla ENC-1 on useita nimiä. 

Related articles in PubMed

1. Up-regulation of the ectodermal-neural cortex 1 (ENC1) gene, a downstream target of the beta-catenin/T-cell factor complex, in colorectal carcinomas. Fujita M, et al. Cancer Res, 2001 Nov 1. PMID 11691783
2. Genomic organization, chromosomal localization and regulation of expression of the neuronal nuclear matrix protein NRP/B in human brain tumors. Kim TA, et al. Gene, 2000 Sep 5. PMID 10974570
3. Transient induction of ENC-1, a Kelch-related actin-binding protein, is required for adipocyte differentiation. Zhao L, et al. J Biol Chem, 2000 Jun 2. PMID 10828068
4. Assignment of the ectodermal-neural cortex 1 gene (ENC1) to human chromosome band 5q13 by in situ hybridization. Hernandez MC, et al. Cytogenet Cell Genet, 1999. PMID 10640818
5. Cloning of human ENC-1 and evaluation of its expression and regulation in nervous system tumors. Hernandez MC, et al. Exp Cell Res, 1998 Aug 1. PMID 9683534

See all (32) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

What's a GeneRIF?

1. ENC1 interacts with the phosphorylated p62 to impair autophagic degradation of mutant huntingtin protein aggregates.
2. we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population.
3. ENC1 functions as a negative regulator of Nrf2 through suppressing Nrf2 protein translation.The transcription factor Nrf2 is the master regulator of a cellular defense mechanism against environmental insults. The Nrf2-mediated antioxidant response is accomplished by the transcription of a battery of genes that encode phase II detoxifying enzymes, xenobiotic transporters, and antioxidants. Coordinated expression of these genes is critical in protecting cells from toxic and carcinogenic insults and in maintaining cellular redox homeostasis. Activation of the Nrf2 pathway is primarily controlled by Kelch-like ECH-associated protein 1 (Keap1), which is a molecular switch that turns on or off the Nrf2 signaling pathway according to intracellular redox conditions. Here we report our finding of a novel Nrf2 suppressor ectodermal-neural cortex 1 (ENC1), which is a BTB-Kelch protein and belongs to the same family as Keap1. Transient expression of ENC1 reduced steady-state levels of Nrf2 and its downstream gene expression. Although ENC1 interacted with Keap1 indirectly, the ENC1-mediated down-regulation of Nrf2 was independent of Keap1. The negative effect of ENC1 on Nrf2 was not due to a change in the stability of Nrf2 because neither proteasomal nor lysosomal inhibitors had any effects. Overexpression of ENC1 did not result in a change in the level of Nrf2 mRNA, rather, it caused a decrease in the rate of Nrf2 protein synthesis. These results demonstrate that ENC1 functions as a negative regulator of Nrf2 through suppressing Nrf2 protein translation, which adds another level of complexity in controlling the Nrf2 signaling pathway
4. NRP/B mutations impair Nrf2-dependent NQO1 induction in primary brain tumors.
5. NRP/B enhances oxidative stress responses in breast cancer cells via the Nrf2 pathway, identifying a novel role of nuclear matrix protein(s) in oxidative stress responses.
6. results suggest that upregulation of ENC-1 contributes to the development of HCL and provides new information on the possible dysregulation of ENC-1 including expression of a novel antisense gene, ENC-1AS

KLHL16 (16q23.2), Gigaxoniini, GAN . Mutaatioiden merkitys.

https://www.ncbi.nlm.nih.gov/gene/8139

Edellisen KLHL1 geenin löytöä  käsittelevän  tekstin sitaatissa oli seuraavat lauseet:  

..."The Kelch-related proteins have diverse functions in cell morphology, cell organization, and gene expression, and function in multiprotein complexes through contact sites in their β-propeller domains (14). Recently, a new member of the BTB/Kelch repeat family, gigaxonin (GAN, KLHL16), was reported to be a pathological target for neurodegenerative disorders in which alterations were found to contain multiple mutations in the Kelch repeats in the neurofilament network (15)." tarkistan viitteen 15:

  https://www.nature.com/articles/ng1100_370
 Published: November 2000

The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy

• Pascale Bomont,
• Laurent Cavalier,et al.

Nature Genetics volume 26, pages370–374(2000)

Abstract

Disorganization of the neurofilament network is a prominent feature of several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy and axonal Charcot-Marie-Tooth disease^1,2,3,4. Giant axonal neuropathy (GAN, MIM 256850), a severe, autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system, is characterized by neurofilament accumulation, leading to segmental distension of the axons^5,6. GAN corresponds to a generalized disorganization of the cytoskeletal intermediate filaments (IFs), to which neurofilaments belong, as abnormal aggregation of multiple tissue-specific IFs has been reported: vimentin in endothelial cells, Schwann cells and cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP) in astrocytes^7,8,9,10,11. Keratin IFs also seem to be alterated, as most patients present characteristic curly or kinky hairs¹².

 We report here identification of the gene GAN, which encodes a novel, ubiquitously expressed protein we have named gigaxonin. We found one frameshift, four nonsense and nine missense mutations in GAN of GAN patients. Gigaxonin is composed of an amino-terminal BTB (for Broad-Complex, Tramtrack and Bric a brac) domain followed by a six kelch repeats, which are predicted to adopt a β-propeller shape¹³. Distantly related proteins sharing a similar domain organization have various functions associated with the cytoskeleton, predicting that gigaxonin is a novel and distinct cytoskeletal protein that may represent a general pathological target for other neurodegenerative disorders with alterations in the neurofilament network.

KLHL1(13q21.33) , MRP2. Oligodendrosyytille tärkeä Mayvenin sukuinen MRP2 = Kelch proteiini 1)

http://www.jbc.org/content/282/16/12319.long
 Tutkijat luonnehtivat uuden Kelch proteiinin joka on KLHL1 kaltainen ja Mayvenin sukuinen MPR2.  Se osoittautuu tärkeäksi merkitsijäksi oligodenrosyyttien elämässä.

Process Elongation of Oligodendrocytes Is Promoted by the Kelch-related Protein MRP2/KLHL1^*

Shuxian Jiang¹, Seyha Seng¹, Hava Karsenty Avraham, Yigong Fu and Shalom Avraham²

1. Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115

1. ↵2 To whom correspondence should be addressed: 4 Blackfan Circle, Boston, MA 02115. Tel.: 617-667-0063; Fax: 617-975-6373 or 617-975-5240; E-mail: savraham{at}bidmc.harvard.edu.

Abstract

Oligodendrocytes (OLGs) are generated by progenitor cells that are committed to differentiating into myelin-forming cells of the central nervous system. Rearrangement of the cytoskeleton leading to the extension of cellular processes is essential for the myelination of axons by OLGs. Here, we have characterized a new member of the Kelch-related protein family termed MRP2 (for Mayven-related protein 2) that is specifically expressed in brain. MRP2/KLHL1 is expressed in oligodendrocyte precursors and mature OLGs, and its expression is up-regulated during OLG differentiation. MRP2/KLHL1 expression was abundant during the specific stages of oligodendrocyte development, as identified by A2B5-, O4-, and O1-specific oligodendrocyte markers. MRP2/KLHL1 was localized in the cytoplasm and along the cell processes. Moreover, a direct endogenous association of MRP2/KLHL1 with actin was observed, which was significantly increased in differentiated OLGs compared with undifferentiated OLGs. Overexpression of MRP2/KLHL1 resulted in a significant increase in the process extension of rat OLGs, whereas MRP2/KLHL1 antisense reduced the process length of primary rat OLGs. Furthermore, murine OLGs isolated from MRP2/KLHL1 transgenic mice showed a significant increase in the process extension of OLGs compared with control wild-type murine OLGs. These studies provide insights into the role of MRP2/KLHL1, through its interaction with actin, in the process elongation of OLGs.

Oligodendrocytes (OLGs)³ are a major cell type in the central nervous system. Development of these cells is necessary for normal functioning of the brain, and injury to them is involved in the pathogenesis of important neurological disorders including cerebral palsy, multiple sclerosis, and periventricular leukomalacia (1, 2). OLGs represent the myelin-forming cells of the central nervous system. They produce numerous membranous processes, which spirally enwrap neuronal axons, forming multilamellar myelin sheaths (3, 4). OLGs are metabolically the most active cells in the brain (5). Before OLGs can remyelinate, they must first be able to extend their processes, and contact the demyelinated axons. However, the molecules involved in the mechanisms of OLG process extension are poorly defined.

A new and unique family of actin-binding proteins with sequences and domains homologous with the Drosophila “Kelch” protein has emerged (6). Kelch protein is believed to be important for the maintenance of the ordered cytoskeleton (7, 8). The Kelch protein has two structural domains that are also found in other molecules. The first domain, which consists of about 115 amino acids, has been named the BTB (Bric-a-brac, Tramtrack, Broad-complex) domain (9) or POZ (Poxvirus zinc finger) domain (10). The second domain, composed of about 50 amino acids repeated in tandem, has been called the “Kelch repeats.” The BTB/POZ domain has been proposed to function as a protein-protein interaction interface, which organizes higher order structures involved in chromatin folding or cytoskeleton organization (11). 

The Kelch-related proteins are a superfamily of proteins conserved in a wide range of organisms, from viruses to mammals. At least 60 Kelch-related proteins have been identified, but their physiological and biochemical functions remain largely uncharacterized (12, 13). The Drosophila Kelch proteins colocalize with actin filaments in a structure called the ring canal, which bridges 15 nurse cells and the oocyte. Drosophila Kelch protein plays an important role in maintaining actin organization during the development of ring canals (6, 8).

The Kelch-related proteins have diverse functions in cell morphology, cell organization, and gene expression, and function in multiprotein complexes through contact sites in their β-propeller domains (14). Recently, a new member of the BTB/Kelch repeat family, gigaxonin (GAN, KLHL16), was reported to be a pathological target for neurodegenerative disorders in which alterations were found to contain multiple mutations in the Kelch repeats in the neurofilament network (15).

We have previously identified and characterized two actinbinding proteins, termed NRP/B/ENC-1 (KLHL37, PIG10 TP5310 ,5q13.3) (16-18) and Mayven (KHLH24q32.3)  (19), predominantly expressed in brain. Mayven is an actin-binding protein that is co-localized with actin filaments in stress fibers and in the patchy cortical actin-rich regions of the cell margins and processes, including the process tips in primary neurons and U373-MG astrocytoma/glioblastoma cells (19). During our study of proteins that are related to Mayven, we identified and cloned a novel gene, which we termed: MRP2 (Mayven-related protein 2) that was found to be identical to KLHL1 (20, 21). In this study, we have investigated the expression of MRP2/KLHL1 in OLGs and its possible role in the dynamics of cytoskeletal rearrangement, leading to the elongation of OLG processes.

Previous SectionNext Section

Oligodendrocytes (OLGs)³ are a major cell type in the central nervous system. Development of these cells is necessary for normal functioning of the brain, and injury to them is involved in the pathogenesis of important neurological disorders including cerebral palsy, multiple sclerosis, and periventricular leukomalacia (1, 2). OLGs represent the myelin-forming cells of the central nervous system. They produce numerous membranous processes, which spirally enwrap neuronal axons, forming multilamellar myelin sheaths (3, 4). OLGs are metabolically the most active cells in the brain (5). Before OLGs can remyelinate, they must first be able to extend their processes, and contact the demyelinated axons. However, the molecules involved in the mechanisms of OLG process extension are poorly defined.

A new and unique family of actin-binding proteins with sequences and domains homologous with the Drosophila “Kelch” protein has emerged (6). Kelch protein is believed to be important for the maintenance of the ordered cytoskeleton (7, 8). The Kelch protein has two structural domains that are also found in other molecules. The first domain, which consists of about 115 amino acids, has been named the BTB (Bric-a-brac, Tramtrack, Broad-complex) domain (9) or POZ (Poxvirus zinc finger) domain (10). The second domain, composed of about 50 amino acids repeated in tandem, has been called the “Kelch repeats.” The BTB/POZ domain has been proposed to function as a protein-protein interaction interface, which organizes higher order structures involved in chromatin folding or cytoskeleton organization (11).

The Kelch-related proteins are a superfamily of proteins conserved in a wide range of organisms, from viruses to mammals. At least 60 Kelch-related proteins have been identified, but their physiological and biochemical functions remain largely uncharacterized (12, 13). The Drosophila Kelch proteins colocalize with actin filaments in a structure called the ring canal, which bridges 15 nurse cells and the oocyte. Drosophila Kelch protein plays an important role in maintaining actin organization during the development of ring canals (6, 8). The Kelch-related proteins have diverse functions in cell morphology, cell organization, and gene expression, and function in multiprotein complexes through contact sites in their β-propeller domains (14). Recently, a new member of the BTB/Kelch repeat family, gigaxonin, was reported to be a pathological target for neurodegenerative disorders in which alterations were found to contain multiple mutations in the Kelch repeats in the neurofilament network (15).

We have previously identified and characterized two actinbinding proteins, termed NRP/B/ENC-1 (16-18) and Mayven (19), predominantly expressed in brain. Mayven is an actin-binding protein that is co-localized with actin filaments in stress fibers and in the patchy cortical actin-rich regions of the cell margins and processes, including the process tips in primary neurons and U373-MG astrocytoma/glioblastoma cells (19). During our study of proteins that are related to Mayven, we identified and cloned a novel gene, which we termed: MRP2 (Mayven-related protein 2) that was found to be identical to KLHL1 (20, 21). In this study, we have investigated the expression of MRP2/KLHL1 in OLGs and its possible role in the dynamics of cytoskeletal rearrangement, leading to the elongation of OLG processes.

KLHL32(6q16.1) Kelch-proteiini ilmentyy miltei yksinomaan keskushermostossa.

 1)  http://www.ebi.ac.uk/interpro/entry/InterPro/IPR030570/
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658946/figure/F1/

2)  https://www.ncbi.nlm.nih.gov/pubmed/23253088

Abstract

Tourette Syndrome (TS) is a neuropsychiatric disorder in children characterized by motor and verbal tics. Although several genes have been suggested in the etiology of TS, the genetic mechanisms remain poorly understood.
Using cytogenetics and FISH analysis, we identified an apparently balanced t(6,22)(q16.2;p13) in a male patient with TS and obsessive-compulsive disorder (OCD). In order to map the breakpoints and to identify additional submicroscopic rearrangements, we performed whole genome mate-pair sequencing and CGH-array analysis on DNA from the proband.
Sequence and CGH array analysis revealed a 400 kb deletion located 1.3 Mb telomeric of the chromosome 6q breakpoint, which has not been reported in controls. The deletion affects three genes (GPR63, NDUFA4 and KLHL32) and overlaps a region previously found deleted in a girl with autistic features and speech delay.
 

 The proband's mother, also a carrier of the translocation, was diagnosed with OCD and shares the deletion. We also describe a further potentially related rearrangement which, while unmapped in Homo sapiens, was consistent with the chimpanzee genome.
We conclude that genome-wide sequencing at relatively low resolution can be used for the identification of submicroscopic rearrangements. We also show that large rearrangements may escape detection using standard analysis of whole genome sequencing data. Our findings further provide a candidate region for TS and OCD on chromosome 6q16.

PMID:

23253088

PMCID:

PMC3556158

DOI:

10.1186/1471-2350-13-123

[Indexed for MEDLINE]

Free PMC Article

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