Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
Sci China Life Sci. 2011 Aug;54(8):770-9. doi: 10.1007/s11427-011-4204-8. Epub 2011 Jul 24.
ALG-2 (a gene product of PDCD6) is a 22-kD protein containing five serially repetitive EF-hand structures and belongs to the penta-EF-hand (PEF) family, including the subunits of typical calpains. ALG-2 is the most conserved protein among the PEF family members and its homologs are widely found in eukaryotes. X-ray crystal structures of various PEF proteins including ALG-2 have common features: presence of eight α-helices and dimer formation via paired EF5s that are positioned in anti-parallel orientation. ALG-2 forms a homodimer and a heterodimer with its closest paralog peflin. Like calmodulin, a well-known four-EF-hand protein, ALG-2 interacts with various proteins in a Ca(2+)-dependent fashion, but the binding motifs are completely different. With some exceptions, ALG-2-interacting proteins commonly contain Pro-rich regions, and ALG-2 recognizes at least two distinct Pro-containing motifs: PPYP(X)nYP (X, variable; n=4 in ALIX and PLSCR3) and PXPGF (represented by Sec31A). A shorter alternatively spliced isoform, lacking two residues and designated ALG-2(ΔGF122), does not bind ALIX but maintains binding capacity to Sec31A. X-ray crystal structural analyses have revealed that binding of calcium ions induces the configuration of the side chain of R125 so that it opens Pocket 1, which accepts PPYP, but Pocket 1 remains closed in the case of ALG-2(ΔGF122). ALG-2 dimer has two ligand-binding sites, each in a monomer molecule, and appears to function as a Ca(2+)-dependent adaptor protein to either stabilize a preformed complex or to bridge two proteins on scaffolds in systems of the endosomal sorting complex required for transport (ESCRT) and ER-to-Golgi transport.
ALG-2（PDCD6 的基因产物）是一种 22kD 的蛋白质，包含五个串联重复的 EF 手结构，属于五 EF 手（PEF）家族，包括典型钙蛋白酶的亚基。ALG-2 是 PEF 家族成员中最保守的蛋白质，其同源物在真核生物中广泛存在。包括 ALG-2 在内的各种 PEF 蛋白的 X 射线晶体结构具有共同的特征：存在八个 α-螺旋和通过位于反平行取向的配对 EF5 形成二聚体。ALG-2 与最接近的同源物 peflin 形成同源二聚体和异源二聚体。像众所周知的四 EF 手蛋白钙调蛋白一样，ALG-2 以 Ca(2+)依赖的方式与各种蛋白质相互作用，但结合基序完全不同。除了一些例外，ALG-2 相互作用的蛋白质通常含有富含脯氨酸的区域，并且 ALG-2 识别至少两个不同的富含脯氨酸的基序：PPYP（X）nYP（X，可变；在 ALIX 和 PLSCR3 中为 n=4）和 PXPGF（以 Sec31A 为代表）。一种较短的选择性剪接异构体，缺失两个残基并命名为 ALG-2（ΔGF122），不与 ALIX 结合，但保持与 Sec31A 的结合能力。X 射线晶体结构分析表明，钙离子的结合诱导 R125 侧链的构象，使其打开接受 PPYP 的口袋 1，但在 ALG-2（ΔGF122）的情况下，口袋 1 保持关闭。ALG-2 二聚体具有两个配体结合位点，每个单体分子各一个，似乎作为 Ca(2+)依赖的衔接蛋白发挥作用，要么稳定预先形成的复合物，要么在内体分选复合物所需的运输（ESCRT）和 ER 到高尔基体运输系统的支架上桥接两个蛋白质。
