Comparative structure analyses of cystine knot-containing molecules with eight aminoacyl ring including glycoprotein hormones (GPH) alpha and beta subunits and GPH-related A2 (GPA2) and B5 (GPB5) molecules
Comparative structure analyses of cystine knot-containing molecules with eight aminoacyl ring including glycoprotein hormones (GPH) alpha and beta subunits and GPH-related A2 (GPA2) and B5 (GPB5) molecules
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DOI：
10.1186/1477-7827-7-90
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发表时间：
2009-08-31
影响因子：
4.4
通讯作者：
Combarnous, Yves
中科院分区：
文献类型：
--
作者：
Alvarez, Eva;Cahoreau, Claire;Combarnous, Yves
背景资料：胱氨酸结（cys-knot）结构存在于相当大量的属于TGF β和糖蛋白激素（GPH）超家族的分泌蛋白和糖蛋白中，其中许多参与生殖的内分泌控制。在这些分子中，cys-knot由二硫键（SS）桥穿透由8、9或10个氨基酸残基形成的环形成，其中四个是形成两个SS桥的半胱氨酸残基。糖蛋白激素促卵泡激素（FSH）、促黄体激素（LH）、促甲状腺激素（TSH）和绒毛膜促性腺激素（CG）是由非共价缔合的α和β亚基组成的异二聚体，所述α和β亚基具有带有8-氨基酰基（8aa）环的cys结。为了更好地了解糖蛋白激素的结构进化，我们检查了具有7个氨基酸的人类8-aa环cys-knot蛋白序列中SS桥的数量和组织（gremlins），9（cerberus，DAN），10（GPA 2，GPB 5，GPH α）和12（GPH β）半胱氨酸残基。讨论：比较表明，常见的GPH-α亚基表现出类似于DAN和GPA 2的SS桥结构，但具有连接α亚基内的额外半胱氨酸的独特桥。环至最N-末端半胱氨酸残基。特定GPH β亚基也表现出与DAN接近的SS桥组织，但它具有两个额外的C-末端半胱氨酸残基，其参与由SS“扣”紧固的“安全带”的形成，确保GPH的异二聚体结构的稳定性。GPA 2和GPB 5不存在可能参与链间SS桥的半胱氨酸残基，GPB 5不具有与GPH β亚基中的安全带同源的序列。8-aa cys-knot蛋白GPA 2和GPB 5预期仅在高于0.1 μ M的浓度下形成异源二聚体：这将与短期旁分泌作用一致，但与循环中稀释后的内分泌作用不一致。因此，GPA 2和GPB 5可以发挥单独的内分泌作用，无论是在发育和/或在成年生活的脊椎动物和无脊椎动物。
Background: Cystine-knot (cys-knot) structure is found in a rather large number of secreted proteins and glycoproteins belonging to the TGFbeta and glycoprotein hormone (GPH) superfamilies, many of which are involved in endocrine control of reproduction. In these molecules, the cys-knot is formed by a disulfide (SS) bridge penetrating a ring formed by 8, 9 or 10 amino-acid residues among which four are cysteine residues forming two SS bridges. The glycoprotein hormones Follicle-Stimulating Hormone (FSH), Luteinizing Hormone (LH), Thyroid-Stimulating Hormone (TSH) and Chorionic Gonadotropin (CG) are heterodimers consisting of non-covalently associated alpha and beta subunits that possess cys-knots with 8-amino-acyl (8aa) rings. In order to get better insight in the structural evolution of glycoprotein hormones, we examined the number and organization of SS bridges in the sequences of human 8-aa-ring cys-knot proteins having 7 (gremlins), 9 (cerberus, DAN), 10 (GPA2, GPB5, GPH alpha) and 12 (GPH beta) cysteine residues in their sequence.Discussion: The comparison indicated that the common GPH-alpha subunit exhibits a SS bridge organization ressembling that of DAN and GPA2 but possesses a unique bridge linking an additional cysteine inside the ring to the most N-terminal cysteine residue. The specific GPHbeta subunits also exhibit a SS bridge organization close to that of DAN but it has two additional C-terminal cysteine residues which are involved in the formation of the "seat belt" fastened by a SS "buckle" that ensures the stability of the heterodimeric structure of GPHs. GPA2 and GPB5 exhibit no cys residue potentially involved in interchain SS bridge and GPB5 does not possess a sequence homologous to that of the seatbelt in GPH beta-subunits. GPA2 and GPB5 are thus not expected to form a stable heterodimer at low concentration in circulation.Summary: The 8-aa cys-knot proteins GPA2 and GPB5 are expected to form a heterodimer only at concentrations above 0.1 microM: this would be consistent with a short-term paracrine role but not with an endocrine role after dilution in circulation. Consequently, GPA2 and GPB5 could exert separate endocrine roles either during development and/or during adult life of both vertebrates and invertebrates.