Poster abstracts
Poster number 32 submitted by Brandon Neel
The structure and dynamics of protocadherin-15 reveal its functionality in inner-ear mechanotransduction
Brandon L. Neel (Department of Chemistry & Biochemistry, & The Ohio State Biochemistry Program), Deepanshu Choudhary, Yoshie Narui, Lahiru N. Wimalasena (Department of Chemistry & Biochemistry), Carissa F. Klanseck, Pedro De-la-Torre, Conghui Chen (Department of Chemistry & Biochemistry), Raul Araya-Secchi (Structural Biophysics, Section for Neutron and X-ray Science, Niels Bohr Institute, University of Copenhagen), Elakkiya Tamilselvan (Department of Chemistry & Biochemistry, & Biophysics Program), Marcos Sotomayor (Department of Chemistry & Biochemistry)
Abstract:
Within the inner ear force generated by sound or head movements is conveyed in part by protocadherin-15 (PCDH15), an atypical member of the cadherin superfamily, which is an essential protein in the opening of mechanically-gated ion channels for the perception of sound, balance, and acceleration. Mutations of PCDH15 are implicated in deafness, progressive blindness, and cancer. Protocadherin-15 is composed of 11 extracellular cadherin (EC) repeats and a membrane adjacent domain (MAD12) and creates a parallel homodimer that interacts with a cadherin-23 (CDH23) homodimer to form the tip-link heterotetramer. The EC repeats are similar in structure but not in sequence, with mechanical strength often provided by conserved calcium-binding linker regions between successive ECs. Here we present ten overlapping crystal structures of EC fragments and the assembled monomeric ectodomain of PCDH15. Some of the calcium-binding regions of PCDH15 are non-canonical and provide flexibility to the ectodomain. The middle portion of PCDH15, comprised of EC4 through EC7, features a highly conserved non-canonical linker region between EC5 and EC6. Molecular dynamics (MD) simulations and two crystal structures (EC4-7 and EC5-7) provide insight into this unique linker region midway along the PCDH15 ectodomain length and suggest that it supplies flexibility and elasticity needed for parallel homodimerization. Utilizing the flexibility of the EC5-6 linker, we built models for the complete atomistic PCDH15 parallel homodimer employing MD simulations and validated crystal contacts. Steered MD simulations of the models predict the strength, elasticity, and calcium-dependent mechanics of tip links. These results provide a first view of PCDH15’s complete ectodomain structure at an atomic level and a glimpse into the molecular mechanics of inner-ear sensory perception.
Keywords: Molecular Dynamics Simulations, Mechanotransduction, Protein Structure