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4xxw

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Revision as of 08:43, 18 December 2019

Crystal structure of mouse Cadherin-23 EC1-2 and Protocadherin-15 EC1-2 splice variant

Structural highlights

4xxw is a 4 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	Pcdh15 (LK3 transgenic mice), Cdh23 (LK3 transgenic mice)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[PCD15_MOUSE] Defects in Pcdh15 are the cause of the Ames waltzer (av) phenotype. It is characterized by deafness and a balance disorder, associated with the degeneration of inner ear neuroepithelia. [CAD23_MOUSE] Defects in Cdh23 are the cause of waltzer (v) phenotype. Waltzer mice are characterized by deafness and vestibular dysfunction due to degeneration of the neuroepithelium within the inner ear.

Function

[PCD15_MOUSE] Calcium-dependent cell-adhesion protein. Required for inner ear neuroepithelial cell elaboration and cochlear function. Probably involved in the maintenance of normal retinal function. [CAD23_MOUSE] Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells. CDH23 is required for establishing and/or maintaining the proper organization of the stereocilia bundle of hair cells in the cochlea and the vestibule during late embryonic/early postnatal development. It is part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal hearing.^[1]

Publication Abstract from PubMed

Human hearing relies upon the tip-to-tip interaction of two nonclassical cadherins, protocadherin-15 (PCDH15) and cadherin-23 (CDH23). Together, these proteins form a filament called the tip link that connects neighboring stereocilia of mechanosensitive hair cells. As sound waves enter the cochlea, the stereocilia deflect and tension is applied to the tip link, opening nearby transduction channels. Disruption of the tip link by loud sound or calcium chelators eliminates transduction currents and illustrates that tip-link integrity is critical for mechanosensing. Tip-link remodeling after disruption is a dynamic process, which can lead to the formation of atypical complexes that incorporate alternatively spliced variants of PCDH15. These variants are categorized into six groups (N1-N6) based upon differences in the first two extracellular cadherin (EC) repeats. Here, we characterized the two N-terminal EC repeats of all PCDH15 variants (pcdh15(N1) to pcdh15(N6)) and combined these variants to test complex formation. We solved the crystal structure of a new complex composed of CDH23 EC1-2 (cdh23) and pcdh15(N2) at 2.3 A resolution and compared it to the canonical cdh23-pcdh15(N1) complex. While there were subtle structural differences, the binding affinity between cdh23 and pcdh15(N2) is approximately 6 times weaker than cdh23 and pcdh15(N1) as determined by surface plasmon resonance analysis. Steered molecular dynamics simulations predict that the unbinding force of the cdh23-pcdh15(N2) complex can be lower than the canonical tip link. Our results demonstrate that alternative heterophilic tip-link structures form stable protein-protein interactions in vitro and suggest that homophilic PCDH15-PCDH15 tip links form through the interaction of additional EC repeats.

Tuning Inner-Ear Tip-Link Affinity Through Alternatively Spliced Variants of Protocadherin-15.,Narui Y, Sotomayor M Biochemistry. 2018 Mar 20;57(11):1702-1710. doi: 10.1021/acs.biochem.7b01075., Epub 2018 Mar 6. PMID:29443515^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Di Palma F, Holme RH, Bryda EC, Belyantseva IA, Pellegrino R, Kachar B, Steel KP, Noben-Trauth K. Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D. Nat Genet. 2001 Jan;27(1):103-7. PMID:11138008 doi:http://dx.doi.org/10.1038/83660
↑ Narui Y, Sotomayor M. Tuning Inner-Ear Tip-Link Affinity Through Alternatively Spliced Variants of Protocadherin-15. Biochemistry. 2018 Mar 20;57(11):1702-1710. doi: 10.1021/acs.biochem.7b01075., Epub 2018 Mar 6. PMID:29443515 doi:http://dx.doi.org/10.1021/acs.biochem.7b01075

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4xxw"

@@ Line 1: / Line 1: @@
 ==Crystal structure of mouse Cadherin-23 EC1-2 and Protocadherin-15 EC1-2 splice variant==
-<StructureSection load='4xxw' size='340' side='right' caption='[[4xxw]], [[Resolution|resolution]] 2.26&Aring;' scene=''>
+<StructureSection load='4xxw' size='340' side='right'caption='[[4xxw]], [[Resolution|resolution]] 2.26&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4xxw]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XXW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XXW FirstGlance]. <br>
@@ Line 23: / Line 23: @@
 ==See Also==
-*[[Cadherin|Cadherin]]
+*[[Cadherin 3D structures|Cadherin 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Lk3 transgenic mice]]
 [[Category: Narui, Y]]

4xxw

From Proteopedia

Revision as of 08:43, 18 December 2019

Crystal structure of mouse Cadherin-23 EC1-2 and Protocadherin-15 EC1-2 splice variant

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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