Merlin (protein)

NF2
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

4ZRJ, 1H4R, 3U8Z, 4ZRI

Identifikatori
AliasiNF2
Vanjski ID-jeviOMIM: 607379 MGI: 97307 HomoloGene: 2180 GeneCards: NF2
Lokacija gena (čovjek)
Hromosom 22 (čovjek)
Hrom.Hromosom 22 (čovjek)[1]
Hromosom 22 (čovjek)
Genomska lokacija za NF2
Genomska lokacija za NF2
Bend22q12.2Početak29,603,556 bp[1]
Kraj29,698,598 bp[1]
Lokacija gena (miš)
Hromosom 11 (miš)
Hrom.Hromosom 11 (miš)[2]
Hromosom 11 (miš)
Genomska lokacija za NF2
Genomska lokacija za NF2
Bend11 A1|11 3.0 cMPočetak4,715,845 bp[2]
Kraj4,799,536 bp[2]
Obrazac RNK ekspresije




Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• cytoskeletal protein binding
• GO:0001948, GO:0016582 vezivanje za proteine
• actin binding
Ćelijska komponenta• citoplazma
• cell body
• projekcija ćelije
• membrana
• Filopodija
• ruffle
• adherens junction
• ćelijska membrana
• apical part of cell
• ruffle membrane
• early endosome
• Jedarce
• cortical actin cytoskeleton
• perinuklearno područje citoplazme
• neuron projection
• cleavage furrow
• citoskelet
• jedro
• lamellipodium
• filopodium membrane
• citosol
Biološki proces• negative regulation of receptor signaling pathway via JAK-STAT
• regulation of gliogenesis
• cell-cell junction organization
• regulation of protein stability
• negative regulation of cell-cell adhesion
• negative regulation of protein kinase activity
• mesoderm formation
• ectoderm development
• negative regulation of DNA replication
• Schwann cell proliferation
• regulation of neural precursor cell proliferation
• regulation of protein localization to nucleus
• negative regulation of cell-matrix adhesion
• odontogenesis of dentin-containing tooth
• brain development
• negative regulation of cell migration
• lens fiber cell differentiation
• regulation of cell population proliferation
• positive regulation of cell differentiation
• negative regulation of MAPK cascade
• regulation of hippo signaling
• hippocampus development
• regulation of stem cell proliferation
• regulation of neurogenesis
• actin cytoskeleton organization
• positive regulation of stress fiber assembly
• negative regulation of cell population proliferation
• negative regulation of tyrosine phosphorylation of STAT protein
• regulation of apoptotic process
• regulation of cell cycle
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

4771

18016

Ensembl

ENSG00000186575

ENSMUSG00000009073

UniProt

P35240

P46662

RefSeq (mRNK)
NM_181835
NM_000268
NM_016418
NM_181825
NM_181826

NM_181827
NM_181828
NM_181829
NM_181830
NM_181831
NM_181832
NM_181833
NM_181834

NM_001252250
NM_001252251
NM_001252252
NM_001252253
NM_010898

NM_001361675
NM_001361676
NM_001361677

RefSeq (bjelančevina)
NP_000259
NP_057502
NP_861546
NP_861966
NP_861967

NP_861968
NP_861969
NP_861970
NP_861971

NP_001239179
NP_001239180
NP_001239181
NP_001239182
NP_035028

NP_001348604
NP_001348605
NP_001348606

Lokacija (UCSC)Chr 22: 29.6 – 29.7 MbChr 11: 4.72 – 4.8 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Merlin, znan i kao neurofibromin 2 ili švanomin, jest citoskeletni protein koji je kod ljudi kodiran genom NF2 sa hromosoma 22. Kod ljudi, to je protein supresije tumora uključen u neurofibromatozu tip II.[5][6] Podaci o sekvenci otkrivaju njegovu sličnost sa ERM porodicom proteina.

Ime "merlin" je akronim za "merlin-erzin-radiksin-liki protein'".

Gen

[uredi | uredi izvor]

Ljudski merlin kodiran je genom NF2 da hromosoma 22. MišJI gen ZE merlin nalazi se na hromosomu 11[7] i pacovski merlin gen na hromosomu 17. Gen za merlin (simbol Mer) kod vinske mušice nalazi se na njenom hromosomu 1 i dijeli 58% sličnosti sa ljudskim homologom. Drugi geni slični merlinskim poznati su iz širokog spektra životinja, a smatra se da je divergencija merlina desila kod ranih Metazoa. Merlin je član ERM porodice proteina uključujući ezrin, mezin i radiksin, koji se nalaze u proteinskoj natporodici protein 4.1. Merlin je također poznat kao švanomin, naziv koji potiče od najčešćeg tipa tumora u fenotipu NF2 pacijenata, švanoma.

Aminokiselinska sekvenca

[uredi | uredi izvor]

Dužina polipeptidnog lanca je 595 aminokiseline, a molekulska težina 69.690 Da.

1020304050
MAGAIASRMSFSSLKRKQPKTFTVRIVTMDAEMEFNCEMKWKGKDLFDLV
CRTLGLRETWFFGLQYTIKDTVAWLKMDKKVLDHDVSKEEPVTFHFLAKF
YPENAEEELVQEITQHLFFLQVKKQILDEKIYCPPEASVLLASYAVQAKY
GDYDPSVHKRGFLAQEELLPKRVINLYQMTPEMWEERITAWYAEHRGRAR
DEAEMEYLKIAQDLEMYGVNYFAIRNKKGTELLLGVDALGLHIYDPENRL
TPKISFPWNEIRNISYSDKEFTIKPLDKKIDVFKFNSSKLRVNKLILQLC
IGNHDLFMRRRKADSLEVQQMKAQAREEKARKQMERQRLAREKQMREEAE
RTRDELERRLLQMKEEATMANEALMRSEETADLLAEKAQITEEEAKLLAQ
KAAEAEQEMQRIKATAIRTEEEKRLMEQKVLEAEVLALKMAEESERRAKE
ADQLKQDLQEAREAERRAKQKLLEIATKPTYPPMNPIPAPLPPDIPSFNL
IGDSLSFDFKDTDMKRLSMEIEKEKVEYMEKSKHLQEQLNELKTEIEALK
LKERETALDILHNENSDRGGSSKHNTIKKLTLQSAKSRVAFFEEL

Struktura

[uredi | uredi izvor]

Merlin kičmenjaka je protein od 70 kDa. Postoji 10 poznatih izoformi molekula ljudskog merlina (punia dužina molekul je 595 aminokiselina). Dva najčešća od njih se takođe nalaze kod miševa i zovu se tip 1 i tip 2, a razlikuju se po odsustvu ili prisustvu egzona 16 ili 17). Sve poznate varijante transkripta imaju konzervirani N-terminalni dio, koji sadrži FERM domen (domen koji se nalazi u većini proteina koji organiziraju citoskeletnu membranu). Nakon FERM domena, slijede alfa-heliksni domen i hidrofilni rep.[8][9] Merlin se može dimerizirati sam sa sobom i heterodimerizirati sa drugim proteinima iz porodice ERM.

Funkcija

[uredi | uredi izvor]

Merlin je protein membranskog-citoskeleta, tj. povezuje aktinske filamente sa ćelijskom membranom ili membranskim glikoproteinima.[10] Ljudski merlin nalazi se pretežno u nervnom tkivu, ali i u nekoliko drugih fetusnih tkiva, uglavnom u čvrstim spojevima.[11] Njegova svojstva supresije tumora su vjerovatno povezana sa inhibicijom rasta posredovanom kontaktom. Kod Drosophila eksprimiran je u embrionskim zadnjim crijevima, pljuvačnim žlijezdama i imaginalnim diskovima i očigledno ima nešto drugačiju ulogu nego kod kičmenjaka.[12]

Poznato je da funkcionalno stanje merlina mijenja fosforilacija serina 518.[13] Predlaže se da signalni put merlina uključuje nekoliko istaknutih molekula za kontrolu rasta ćelija, uključujući eIF3c, CD44, protein kinazu A i p21 aktiviranu kinazu.

Rad na rodu Drosophila identifikovao je merlina kao uzvodnog regulatora puta supresora tumora nilskog konja,[14] funkcije koja je konzervirana kod sisara.[15] Hippo put je dobro konzrervirani signalni put koji koordiniramo reguliše ćelijsku proliferaciju i apoptoze.[16]

Mutacije gena NF2 uzrokuju autosomno dominantnu bolest kod ljudi zvanu neurofibromatoza tip 2. Karakterizira je razvoj tumora nervnog sistema, najčešće bilateralnih vestibulumskih švanoma (koji se također nazivaju slušni neuromi). NF2 pripada grupi tumorskih supresora.[17]

Interakcije

[uredi | uredi izvor]

Pokazalo se da merlinskiprotein reaguje sa:

Reference

[uredi | uredi izvor]
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000186575 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000009073 - Ensembl, maj 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B (1993). "Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2". Nature. 363 (6429): 515–21. Bibcode:1993Natur.363..515R. doi:10.1038/363515a0. PMID 8379998.
  6. ^ Golovnina K, Blinov A, Akhmametyeva EM, Omelyanchuk LV, Chang LS (2005). "Evolution and origin of merlin, the product of the Neurofibromatosis type 2 (NF2) tumor-suppressor gene". BMC Evol. Biol. 5: 69. doi:10.1186/1471-2148-5-69. PMC 1315344. PMID 16324214.
  7. ^ Haase VH, Trofatter JA, MacCollin M, Tarttelin E, Gusella JF, Ramesh V (1994). "The murine NF2 homologue encodes a highly conserved merlin protein with alternative forms". Hum. Mol. Genet. 3 (3): 407–11. doi:10.1093/hmg/3.3.407. PMID 8012352.
  8. ^ Shimizu T, Seto A, Maita N, Hamada K, Tsukita S, Tsukita S, Hakoshima T (2002). "Structural basis for neurofibromatosis type 2. Crystal structure of the merlin FERM domain". J. Biol. Chem. 277 (12): 10332–6. doi:10.1074/jbc.M109979200. PMID 11756419.
  9. ^ Ali Khajeh, J; Ju, JH; Atchiba, M (2014). "Molecular conformation of the full-length tumor suppressor NF2/Merlin--a small-angle neutron scattering study". Journal of Molecular Biology. 426 (15): 2755–68. doi:10.1016/j.jmb.2014.05.011. PMC 4407695. PMID 24882693.
  10. ^ McClatchey AI, Giovannini M (2005). "Membrane organization and tumorigenesis--the NF2 tumor suppressor, Merlin". Genes Dev. 19 (19): 2265–77. doi:10.1101/gad.1335605. PMID 16204178.
  11. ^ den Bakker MA, Vissers KJ, Molijn AC, Kros JM, Zwarthoff EC, van der Kwast TH (1999). "Expression of the neurofibromatosis type 2 gene in human tissues". J. Histochem. Cytochem. 47 (11): 1471–80. doi:10.1177/002215549904701113. PMID 10544220. Arhivirano s originala, 18. 5. 2008.
  12. ^ LaJeunesse DR, McCartney BM, Fehon RG (1998). "Structural Analysis of Drosophila Merlin Reveals Functional Domains Important for Growth Control and Subcellular Localization". J. Cell Biol. 141 (7): 1589–99. doi:10.1083/jcb.141.7.1589. PMC 2133006. PMID 9647651.
  13. ^ Alfthan K, Heiska L, Grönholm M, Renkema GH, Carpén O (2004). "Cyclic AMP-dependent protein kinase phosphorylates merlin at serine 518 independently of p21-activated kinase and promotes merlin-ezrin heterodimerization". J. Biol. Chem. 279 (18): 18559–66. doi:10.1074/jbc.M313916200. PMID 14981079.
  14. ^ Hamaratoglu F, Willecke M, Kango-Singh M, et al. (2006). "The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis". Nature Cell Biology. 8 (1): 27–36. doi:10.1038/ncb1339. PMID 16341207.
  15. ^ Zhang N, Bai H, David KK, Dong J, Zheng Y, Cai J, Giovannini M, Liu P, Anders RA, Pan D (2010). "The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals". Developmental Cell. 19 (1): 27–38. doi:10.1016/j.devcel.2010.06.015. PMC 2925178. PMID 20643348.
  16. ^ Pan D (oktobar 2010). "The hippo signaling pathway in development and cancer". Developmental Cell. 19 (4): 491–505. doi:10.1016/j.devcel.2010.09.011. PMC 3124840. PMID 20951342.
  17. ^ Scoles DR, Yong WH, Qin Y, Wawrowsky K, Pulst SM (2006). "Schwannomin inhibits tumorigenesis through direct interaction with the eukaryotic initiation factor subunit c (eIF3c)". Hum. Mol. Genet. 15 (7): 1059–70. doi:10.1093/hmg/ddl021. PMID 16497727.
  18. ^ a b c d Huang J, Chen J (juli 2008). "VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation". Oncogene. 27 (29): 4056–64. doi:10.1038/onc.2008.44. PMID 18332868.
  19. ^ Grönholm M, Sainio M, Zhao F, Heiska L, Vaheri A, Carpén O (mart 1999). "Homotypic and heterotypic interaction of the neurofibromatosis 2 tumor suppressor protein merlin and the ERM protein ezrin". J. Cell Sci. 112 (6): 895–904. PMID 10036239.
  20. ^ Gutmann DH, Haipek CA, Burke SP, Sun CX, Scoles DR, Pulst SM (april 2001). "The NF2 interactor, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), associates with merlin in the "open" conformation and suppresses cell growth and motility". Hum. Mol. Genet. 10 (8): 825–34. doi:10.1093/hmg/10.8.825. PMID 11285248.
  21. ^ Scoles DR, Huynh DP, Chen MS, Burke SP, Gutmann DH, Pulst SM (juli 2000). "The neurofibromatosis 2 tumor suppressor protein interacts with hepatocyte growth factor-regulated tyrosine kinase substrate". Hum. Mol. Genet. 9 (11): 1567–74. doi:10.1093/hmg/9.11.1567. PMID 10861283.
  22. ^ Wiederhold T, Lee MF, James M, Neujahr R, Smith N, Murthy A, Hartwig J, Gusella JF, Ramesh V (novembar 2004). "Magicin, a novel cytoskeletal protein associates with the NF2 tumor suppressor merlin and Grb2". Oncogene. 23 (54): 8815–25. doi:10.1038/sj.onc.1208110. PMID 15467741.
  23. ^ Jannatipour M, Dion P, Khan S, Jindal H, Fan X, Laganière J, Chishti AH, Rouleau GA (august 2001). "Schwannomin isoform-1 interacts with syntenin via PDZ domains". J. Biol. Chem. 276 (35): 33093–100. doi:10.1074/jbc.M105792200. PMID 11432873.
  24. ^ Neill GW, Crompton MR (septembar 2001). "Binding of the merlin-I product of the neurofibromatosis type 2 tumour suppressor gene to a novel site in beta-fodrin is regulated by association between merlin domains". Biochem. J. 358 (Pt 3): 727–35. doi:10.1042/0264-6021:3580727. PMC 1222106. PMID 11535133.

Vanjski linkovi

[uredi | uredi izvor]
Preuzeto iz "https://bs.wikipedia.org/w/index.php?title=Merlin_(protein)&oldid=3547493"