Structural basis for variant-specific neuroligin-binding by ?-neurexin.

ABSTRACT: Neurexins (Nrxs) are presynaptic membrane proteins with a single membrane-spanning domain that mediate asymmetric trans-synaptic cell adhesion by binding to their postsynaptic receptor neuroligins. ?-Nrx has a large extracellular region comprised of multiple copies of laminin, neurexin, sex-hormone-binding globulin (LNS) domains and epidermal growth factor (EGF) modules, while that of ?-Nrx has but a single LNS domain. It has long been known that the larger ?-Nrx and the shorter ?-Nrx show distinct binding behaviors toward different isoforms/variants of neuroligins, although the underlying mechanism has yet to be elucidated. Here, we describe the crystal structure of a fragment corresponding to the C-terminal one-third of the Nrx1? ectodomain, consisting of LNS5-EGF3-LNS6. The 2.3 Å-resolution structure revealed the presence of a domain configuration that was rigidified by inter-domain contacts, as opposed to the more common flexible "beads-on-a-string" arrangement. Although the neuroligin-binding site on the LNS6 domain was completely exposed, the location of the ?-Nrx specific LNS5-EGF3 segment proved incompatible with the loop segment inserted in the B+ neuroligin variant, which explains the variant-specific neuroligin recognition capability observed in ?-Nrx. This, combined with a low-resolution molecular envelope obtained by a single particle reconstruction performed on negatively stained full-length Nrx1? sample, allowed us to derive a structural model of the ?-Nrx ectodomain. This model will help us understand not only how the large ?-Nrx ectodomain is accommodated in the synaptic cleft, but also how the trans-synaptic adhesion mediated by ?- and ?-Nrxs could differentially affect synaptic structure and function.

SUBMITTER: Tanaka H 

PROVIDER: S-EPMC3084293 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature