Structures and functions of penta-EF-hand calcium-binding proteins and their interacting partners: enigmatic relationships between ALG-2 and calpain-7.

The penta-EF-hand (PEF) protein family includes ALG-2 (gene name, PDCD6 ) and its paralogs as well as classical calpain family members. ALG-2 is a prototypic PEF protein that is widely distributed in eukaryotes and interacts with a variety of proteins in a Ca ²⁺ -dependent manner. Mammalian ALG-2 and its interacting partners have various modulatory roles including roles in cell death, signal transduction, membrane repair, ER-to-Golgi vesicular transport, and RNA processing. Some ALG-2-interacting proteins are key factors that function in the endosomal sorting complex required for transport (ESCRT) system. On the other hand, mammalian calpain-7 (CAPN7) lacks the PEF domain but contains two microtubule-interacting and trafficking (MIT) domains in tandem. CAPN7 interacts with a subset of ESCRT-III proteins through the MIT domains and regulates EGF receptor downregulation. Structures and functions of ALG-2 and those of its interacting partners as well as relationships with the calpain family are reviewed in this article.