SUMMARY Rapid neurotransmitter release depends on the Ca2+-sensor Synaptotagmin-1 and the SNARE complex formed by synaptobrevin, syntaxin-1 and SNAP-25. How Synaptotagmin-1 triggers release remains unclear, in part because elucidating high-resolution structures of Synaptotagmin-1-SNARE complexes has been challenging. An NMR approach based on lanthanide-induced pseudocontact shifts now reveals a dynamic binding mode where basic residues in the concave side of the Synaptotagmin-1 C2B domain β-sandwich interact with a polyacidic region of the SNARE complex formed by syntaxin-1 and SNAP-25. The physiological relevance of this dynamic structural model is supported by mutations in basic residues of Synaptotagmin-1 that markedly impair SNARE-complex binding in vitro and Synaptotagmin-1 function in neurons. Mutations with milder effects on binding have correspondingly milder effects on Synaptotagmin-1 function. Our results support a model whereby their dynamic interaction facilitates cooperation between synaptotagmin-1 and the SNAREs in inducing membrane fusion.

The concept of allostery has evolved in the past century. In this Editorial, we briefly overview the history of allostery, from the pre-allostery nomenclature era starting with the Bohr effect (1904) to the birth of allostery by Monod and Jacob (1961). We describe the evolution of the allostery concept, from a conformational change in a two-state model (1965, 1966) to dynamic allostery in the ensemble model (1999); from multi-subunit (1965) proteins to all proteins (2004). We highlight the current available methods to study allostery and their applications in studies of conformational mechanisms, disease, and allosteric drug discovery. We outline the challenges and future directions that we foresee. Altogether, this Editorial narrates the history of this fundamental concept in the life sciences, its significance, methodologies to detect and predict it, and its application in a broad range of living systems.

Four CatSper ion channel subunit genes (CatSpers 1-4) are required for sperm cell hyperactivation and male fertility. The four proteins assemble (presumably as a tetramer) to form a sperm-specific, alkalinization-activated Ca 2؉ -selective channel. We set out to identify proteins associating with CatSper that might help explain its unique role in spermatozoa. Using a transgenic approach, a CatSper1 complex was purified from mouse testis that contained heat shock protein 70-2, a testisspecific chaperone, and CatSper␤, a novel protein with two putative transmembrane-spanning domains. Like the CatSper ion channel subunits, CatSper␤ was restricted to testis and localized to the principal piece of the sperm tail. CatSper␤ protein is absent in CatSper1 ؊/؊ sperm, suggesting that it is required for trafficking or formation of a stable channel complex. CatSper␤ is the first identified auxiliary protein to the CatSper channel.