Publications by authors named "Elakkiya Tamilselvan"

2 Publications

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A complete Protocadherin-19 ectodomain model for evaluating epilepsy-causing mutations and potential protein interaction sites.

Structure 2021 Oct 13;29(10):1128-1143.e4. Epub 2021 Sep 13.

Department of Science and Mathematics, Cedarville University, 251 N. Main Street, Cedarville, OH 45314, USA. Electronic address:

Cadherin superfamily members play a critical role in differential adhesion during neurodevelopment, and their disruption has been linked to several neurodevelopmental disorders. Mutations in protocadherin-19 (PCDH19), a member of the δ-protocadherin subfamily of cadherins, cause a unique form of epilepsy called PCDH19 clustering epilepsy. While PCDH19 and other non-clustered δ-protocadherins form multimers with other members of the cadherin superfamily to alter adhesiveness, the specific protein surfaces responsible for these interactions are unknown. Only portions of the PCDH19 extracellular domain structure had been solved previously. Here, we present a structure of the missing segment from zebrafish Protocadherin-19 (Pcdh19) and create a complete ectodomain model. This model shows the structural environment for 97% of disease-causing missense mutations and reveals two potential surfaces for intermolecular interactions that could modify Pcdh19's adhesive strength and specificity.
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October 2021

Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception.

Proc Natl Acad Sci U S A 2020 10 22;117(40):24837-24848. Epub 2020 Sep 22.

Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210;

The vertebrate inner ear, responsible for hearing and balance, is able to sense minute mechanical stimuli originating from an extraordinarily broad range of sound frequencies and intensities or from head movements. Integral to these processes is the tip-link protein complex, which conveys force to open the inner-ear transduction channels that mediate sensory perception. Protocadherin-15 and cadherin-23, two atypically large cadherins with 11 and 27 extracellular cadherin (EC) repeats, are involved in deafness and balance disorders and assemble as parallel homodimers that interact to form the tip link. Here we report the X-ray crystal structure of a protocadherin-15 + cadherin-23 heterotetrameric complex at 2.9-Å resolution, depicting a parallel homodimer of protocadherin-15 EC1-3 molecules forming an antiparallel complex with two cadherin-23 EC1-2 molecules. In addition, we report structures for 10 protocadherin-15 fragments used to build complete high-resolution models of the monomeric protocadherin-15 ectodomain. Molecular dynamics simulations and validated crystal contacts are used to propose models for the complete extracellular protocadherin-15 parallel homodimer and the tip-link bond. Steered molecular dynamics simulations of these models suggest conditions in which a structurally diverse and multimodal protocadherin-15 ectodomain can act as a stiff or soft gating spring. These results reveal the structural determinants of tip-link-mediated inner-ear sensory perception and elucidate protocadherin-15's structural and adhesive properties relevant in disease.
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October 2020