Merlin (protein)

NF2
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	4ZRJ, 1H4R, 3U8Z, 4ZRI
Identifikatori
Aliasi	NF2
Vanjski ID-jevi	OMIM: 607379 MGI: 97307 HomoloGene: 2180 GeneCards: NF2
Lokacija gena (čovjek)
Hrom.	Hromosom 22 (čovjek)
Kraj	29,698,598 bp
Lokacija gena (miš)
Hrom.	Hromosom 11 (miš)
Kraj	4,799,536 bp
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
	4771
	18016
	ENSG00000186575
	ENSMUSG00000009073
	P35240
	P46662
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
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
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/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

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

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

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MAGAIASRMS	FSSLKRKQPK	TFTVRIVTMD	AEMEFNCEMK	WKGKDLFDLV
CRTLGLRETW	FFGLQYTIKD	TVAWLKMDKK	VLDHDVSKEE	PVTFHFLAKF
YPENAEEELV	QEITQHLFFL	QVKKQILDEK	IYCPPEASVL	LASYAVQAKY
GDYDPSVHKR	GFLAQEELLP	KRVINLYQMT	PEMWEERITA	WYAEHRGRAR
DEAEMEYLKI	AQDLEMYGVN	YFAIRNKKGT	ELLLGVDALG	LHIYDPENRL
TPKISFPWNE	IRNISYSDKE	FTIKPLDKKI	DVFKFNSSKL	RVNKLILQLC
IGNHDLFMRR	RKADSLEVQQ	MKAQAREEKA	RKQMERQRLA	REKQMREEAE
RTRDELERRL	LQMKEEATMA	NEALMRSEET	ADLLAEKAQI	TEEEAKLLAQ
KAAEAEQEMQ	RIKATAIRTE	EEKRLMEQKV	LEAEVLALKM	AEESERRAKE
ADQLKQDLQE	AREAERRAKQ	KLLEIATKPT	YPPMNPIPAP	LPPDIPSFNL
IGDSLSFDFK	DTDMKRLSME	IEKEKVEYME	KSKHLQEQLN	ELKTEIEALK
LKERETALDI	LHNENSDRGG	SSKHNTIKKL	TLQSAKSRVA	FFEEL

Struktura

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

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

Pokazalo se da merlinskiprotein reaguje sa:

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000186575 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000009073 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ ^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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000186575 - Ensembl, maj 2017

[refGRCm38Ensembl-2] 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.

[pmid8379998-5] 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.

[pmid16324214-6] 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.

[pmid8012352-7] 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.

[pmid11756419-8] 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.

[pmid16204178-10] 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.

[pmid10544220-11] 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.

[pmid9647651-12] 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.

[pmid14981079-13] 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.

[pmid16497727-17] 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.

[pmid18332868-18] 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.

[pmid10036239-19] 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.

[pmid11285248-20] 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.

[pmid10861283-21] 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.

[pmid15467741-22] 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.

[pmid11432873-23] 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.

[pmid11535133-24] 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.

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