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Crystal structure of Dscam1 isoform 1.9, N-terminal four Ig domains
Structural highlights
FunctionDSCA1_DROME Cell surface receptor involved in guidance and targeting of growing nerve axons (PubMed:10892653). Required during Bolwig's organ differentiation for accurate and efficient targeting of photoreceptor neuron axons to their synaptic targets in the brain via the P2 intermediate target neuron (PubMed:10892653). Involved in isoneural self-avoidance during dendrite arborization but not in heteroneural recognition and repulsion during tiling by related neurons of the same class (PubMed:17482551). Involved in regulating axon bifurcation and divergent extension in the developing mushroom body (PubMed:11856530, PubMed:15339648). Essential for axon arborisation in ellipsoid body (PubMed:11856530, PubMed:15339648). Exhibits an extraordinary level of molecular diversity resulting from alternative splicing (PubMed:10892653). Isoforms differing in their ectodomain makeup show a high degree of functional redundancy while isoforms with different transmembrane domains are involved in different neuronal morphogenetic processes and are differentially targeted to dendrites or axons (PubMed:15339648). The vast majority of isoforms exhibit strong isoform-specific homophilic binding (PubMed:15339666, PubMed:17889655). Individual cells express a distinct randomly generated repertoire of isoforms (PubMed:14758360). Cell surfaces bearing identical repertoires of Dscam1 isoforms, such as those from the same cell, trigger recognition and avoidance (PubMed:17482551). A subset of isoforms is expressed in fat body cells and hemocytes, cells that are part of the insect immune response, and these isoforms are secreted into the hemolymph (PubMed:16109846). The secreted form comprising the ectodomain can bind to bacteria, such as Escherichia coli, and may act as an opsonin enhancing their phagocytosis by hemocytes (PubMed:16109846).[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedThe Drosophila neural receptor Dscam1 (Down syndrome cell adhesion molecule 1) plays an essential role in neuronal wiring and self-avoidance. Dscam1 potentially encodes 19,008 ectodomains through alternative RNA splicing and exhibits exquisite isoform-specific homophilic binding, which makes it an exceptional example for studying protein binding specificity. However, structural information on Dscam1 is limited, which hinders illumination of the mechanism of Dscam1 isoform-specific recognition. Whether different Dscam1 isoforms adopt the same dimerization mode remains a subject of debate. We present 12 Dscam1 crystal structures, provide direct evidence indicating that all isoforms adopt a conserved homodimer geometry in a modular fashion, identify two mechanisms for the Ig2 binding domain to dispel electrostatic repulsion during dimerization, decode Ig2 binding specificity by a central motif at its symmetry center, uncover the role of glycosylation in Dscam1 homodimerization, and find electrostatic potential complementarity to help define the binding region and the antiparallel binding mode. We then propose a concept that the context of a protein may set restrictions to regulate its binding specificity, which provides a better understanding of protein recognition. Structural basis of Dscam1 homodimerization: Insights into context constraint for protein recognition.,Li SA, Cheng L, Yu Y, Chen Q Sci Adv. 2016 May 27;2(5):e1501118. doi: 10.1126/sciadv.1501118. eCollection 2016, May. PMID:27386517[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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