{"id":279,"date":"2017-01-18T12:50:30","date_gmt":"2017-01-18T11:50:30","guid":{"rendered":"http:\/\/lbti.cnrs.fr\/?page_id=279"},"modified":"2021-04-21T19:26:09","modified_gmt":"2021-04-21T17:26:09","slug":"xxxxxxxx","status":"publish","type":"page","link":"https:\/\/lbti.ibcp.fr\/?page_id=279","title":{"rendered":"M\u00e9canismes mol\u00e9culaires de l\u2019assemblage du collag\u00e8ne"},"content":{"rendered":"\n
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Porteur de projet\u00a0<\/strong><\/em>\u00a0: C. Moali et S. Vadon-Le Goff<\/span>
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La formation des fibres de collag\u00e8ne est un processus complexe impliquant \u00e0 la fois des \u00e9tapes intracellulaires et extracellulaires.<\/span><\/p>\n

\u2022 <\/strong>Au niveau intracellulaire, les chaines polypeptidiques sont synth\u00e9tis\u00e9es, modifi\u00e9es par plusieurs types de modifications post-traductionnelles (hydroxylations, glycosylations, ponts disulfures etc) et assembl\u00e9es en trim\u00e8re de procollag\u00e8nes. Cette derni\u00e8re \u00e9tape est cruciale car elle implique la reconnaissance sp\u00e9cifique des chaines avec la bonne composition et st\u0153chiom\u00e9trie pour garantir qu\u2019une cellule qui synth\u00e9tise plusieurs types de collag\u00e8nes ne produira pas de mol\u00e9cules chim\u00e9riques non fonctionnelles. Ce m\u00e9canisme de reconnaissance est contr\u00f4l\u00e9 pour les collag\u00e8nes fibrillaires par le domaine C-terminal appel\u00e9 C-propeptide.<\/span><\/p>\n

Un de nos th\u00e8mes de recherche consiste \u00e0 comprendre les d\u00e9tails mol\u00e9culaires qui gouvernent ces processus de reconnaissance au niveau des diff\u00e9rents C-propeptides et comment les mutations qui affectent ces domaines peuvent conduire \u00e0 des maladies g\u00e9n\u00e9tiques (Ost\u00e9ogen\u00e8se Imparfaite, Chondrodysplasies, Ehlers-Danlos etc).<\/span><\/p>\n

\u2022 <\/strong>Au niveau extracellulaire, apr\u00e8s s\u00e9cr\u00e9tion des mol\u00e9cules de procollag\u00e8nes, des maturations prot\u00e9olytiques sont n\u00e9cessaires pour diminuer leur solubilit\u00e9 et d\u00e9clencher la formation des fibres. Les principales prot\u00e9ases impliqu\u00e9es sont les prot\u00e9ases BMP-1\/tolloid-like (BTPs), m\u00e9prines et ADAMTS-2, 3 et 14. Les BTPs sont assist\u00e9es par une glycoprot\u00e9ine de 50 kDa nomm\u00e9e Procollagen C-Proteinase Enhancer-1 (PCPE-1) qui peut augmenter significativement l\u2019efficacit\u00e9 des clivages. De fa\u00e7on int\u00e9ressante, PCPE-1 est sp\u00e9cifique des procollag\u00e8nes, sans affecter le clivage des autres substrats des BTPs, et permet d\u2019acc\u00e9l\u00e9rer fortement la formation des fibres de collag\u00e8nes dans certains contextes physiopathologiques (d\u00e9veloppement, r\u00e9paration tissulaire\u2026).<\/span><\/p>\n

Nous essayons de comprendre comment fonctionnent les complexes prot\u00e9olytiques, \u00e0 deux (prot\u00e9ase-substrat, substrat-activateur, prot\u00e9ase-activateur) ou trois (prot\u00e9ase-substrat-activateur) partenaires, impliqu\u00e9s dans la maturation des procollag\u00e8nes fibrillaires.<\/span><\/p>\n

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(A) Structure cristallographique du complexe entre le C-propeptide du collag\u00e8ne III et la partie active de la prot\u00e9ine PCPE-1 (CUB1CUB2). (B) Mod\u00e8le d’une cha\u00eene de procollag\u00e8ne III dans le site catalytique de la m\u00e9talloprot\u00e9ase BMP-1. (C) Mod\u00e8le global du complexe de maturation prot\u00e9olytique des procollag\u00e8nes. (D’apr\u00e8s Pulido et al. Structure 2018).<\/span><\/em><\/p>\n

\u00a0<\/span><\/em><\/p>\n

Principales techniques utilis\u00e9es<\/u><\/span><\/p>\n

\u2022 <\/strong>Production et purification de prot\u00e9ines en cellules eucaryotes<\/span><\/p>\n

\u2022 <\/strong>Enzymologie<\/span><\/p>\n

\u2022 <\/strong>R\u00e9sonance plasmonique de surface \/ fluorescence \/ dichro\u00efsme circulaire<\/span><\/p>\n

\u2022 <\/strong>Spectrom\u00e9trie de masse<\/span><\/p>\n

\u2022 <\/strong>Diffusion des rayons X<\/span><\/p>\n

\u2022 <\/strong>Cryo-microscopie \u00e9lectronique<\/span><\/p>\n

\u2022 <\/strong>Cristallographie<\/span><\/p>\n

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S\u00e9lection de publications<\/em><\/strong>\u00a0\u00a0:<\/em><\/strong><\/span><\/p>\n

Structural basis of fibrillar collagen trimerization and related genetic disorders<\/a>. Bourhis JM, Mariano N, Zhao Y, Harlos K, Exposito JY, Jones EY, Moali C, Aghajari N, Hulmes DJ. Nat Struct Mol Biol. 2012, 19(10):1031-6<\/span><\/p>\n

Procollagen C-proteinase enhancer grasps the stalk of the C-propeptide trimer to boost collagen precursor maturation.<\/a> Bourhis JM, Vadon-Le Goff S, Afrache H, Mariano N, Kronenberg D, Thielens N, Moali C, Hulmes DJ. Proc Natl Acad Sci U S A. 2013, 110(16):6394-9<\/span><\/p>\n

Clinical, structural, biochemical and X-ray crystallographic correlates of pathogenicity for variants in the C-propeptide region of the COL3A1 gene.<\/a> Stembridge NS, Vandersteen AM, Ghali N, Sawle P, Nesbitt M, Pollitt RC, Ferguson DJ, Holden S, Elmslie F, Henderson A, Hulmes DJ, Pope FM. Am J Med Genet A. 2015, 167A(8):1763-72.<\/span><\/p>\n

Structural basis of homo- and heterotrimerization of collagen I.<\/a> Sharma U, Carrique L, Vadon-Le Goff S, Mariano N, Georges RN, Delolme F, Koivunen P, Myllyharju J, Moali C, Aghajari N, Hulmes DJ. Nat Commun. 2017, 8:14671. <\/span><\/p>\n

Structural basis for the acceleration of procollagen processing by procollagen C-proteinase enhancer-1. Pulido D, Sharma U, Vadon-Le Goff S, Hussain SA, Cordes S, Mariano N, Bettler E, Moali C, Aghajari N, Hohenester E, Hulmes DJ. Structure 2018, 26: 1384-92<\/span>.<\/p>\n

\u00a0<\/span><\/p>\n<\/div>\n\n\n\n

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Porteur de projet\u00a0\u00a0: C. Moali et S. Vadon-Le Goff La formation des fibres de collag\u00e8ne est un processus complexe impliquant \u00e0 la fois des \u00e9tapes intracellulaires et extracellulaires. \u2022 Au niveau intracellulaire, les chaines polypeptidiques sont synth\u00e9tis\u00e9es, modifi\u00e9es par plusieurs types de modifications post-traductionnelles (hydroxylations, glycosylations, ponts disulfures etc) et assembl\u00e9es en trim\u00e8re de procollag\u00e8nes.<\/p>\n","protected":false},"author":2,"featured_media":0,"parent":105,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"class_list":["post-279","page","type-page","status-publish","hentry"],"acf":[],"_links":{"self":[{"href":"https:\/\/lbti.ibcp.fr\/index.php?rest_route=\/wp\/v2\/pages\/279","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/lbti.ibcp.fr\/index.php?rest_route=\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/lbti.ibcp.fr\/index.php?rest_route=\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/lbti.ibcp.fr\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/lbti.ibcp.fr\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=279"}],"version-history":[{"count":31,"href":"https:\/\/lbti.ibcp.fr\/index.php?rest_route=\/wp\/v2\/pages\/279\/revisions"}],"predecessor-version":[{"id":4603,"href":"https:\/\/lbti.ibcp.fr\/index.php?rest_route=\/wp\/v2\/pages\/279\/revisions\/4603"}],"up":[{"embeddable":true,"href":"https:\/\/lbti.ibcp.fr\/index.php?rest_route=\/wp\/v2\/pages\/105"}],"wp:attachment":[{"href":"https:\/\/lbti.ibcp.fr\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=279"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}