6MFO

Crystal Structure of Human Protocadherin-15 EC1-3 G16D N369D Q370N

Summary for 6MFO

• Entry DOI: 10.2210/pdb6mfo/pdb
• Descriptor: Protocadherin-15, CALCIUM ION (3 entities in total)
• Functional Keywords: mechanotransduction, calcium-binding protein, stereocilia, hair cell, tip link, cell adhesion
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 43269.55

Authors

Choudhary, D.,Sotomayor, M. (deposition date: 2018-09-11, release date: 2019-09-18, Last modification date: 2024-10-30)

Primary citation

Choudhary, D.,Narui, Y.,Neel, B.L.,Wimalasena, L.N.,Klanseck, C.F.,De-la-Torre, P.,Chen, C.,Araya-Secchi, R.,Tamilselvan, E.,Sotomayor, M.
Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception.
Proc.Natl.Acad.Sci.USA, 2020

PubMed Abstract: 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.

PubMed: 32963095
DOI: 10.1073/pnas.1920444117

Experimental method

X-RAY DIFFRACTION (3.15 Å)