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PDBsum entry 6eet
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Cell adhesion
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PDB id
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6eet
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References listed in PDB file
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Key reference
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Title
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Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception.
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Authors
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D.Choudhary,
Y.Narui,
B.L.Neel,
L.N.Wimalasena,
C.F.Klanseck,
P.De-La-Torre,
C.Chen,
R.Araya-Secchi,
E.Tamilselvan,
M.Sotomayor.
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Ref.
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Proc Natl Acad Sci U S A, 2020,
117,
24837-24848.
[DOI no: ]
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PubMed id
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Abstract
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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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