6PYX

Calcium Activated Chloride Channel Regulator 1 (CLCA1) VWA Domain

Summary for 6PYX

• Entry DOI: 10.2210/pdb6pyx/pdb
• Related: 6PYO
• Descriptor: cDNA FLJ56608, highly similar to Homo sapiens chloride channel, calcium activated, family member 1 (CLCA1), mRNA, CALCIUM ION (3 entities in total)
• Functional Keywords: chloride channel regulator, ion channel regulator, vwa domain, protein transport
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 39694.51

Authors

Brett, T.J.,Berry, K.B. (deposition date: 2019-07-31, release date: 2020-01-29, Last modification date: 2024-11-06)

Primary citation

Berry, K.N.,Brett, T.J.
Structural and Biophysical Analysis of the CLCA1 VWA Domain Suggests Mode of TMEM16A Engagement.
Cell Rep, 30:1141-1151.e3, 2020

PubMed Abstract: The secreted protein calcium-activated chloride channel regulator 1 (CLCA1) utilizes a von Willebrand factor type A (VWA) domain to bind to and potentiate the calcium-activated chloride channel TMEM16A. To gain insight into this unique potentiation mechanism, we determined the 2.0-Å crystal structure of human CLCA1 VWA bound to Ca. The structure reveals the metal-ion-dependent adhesion site (MIDAS) in a high-affinity "open" conformation, engaging in crystal contacts that likely mimic how CLCA1 engages TMEM16A. The CLCA1 VWA contains a disulfide bond between α3 and α4 in close proximity to the MIDAS that is invariant in the CLCA family and unique in VWA structures. Further biophysical studies indicate that CLCA1 VWA is preferably stabilized by Mg over Ca and that α6 atypically extends from the VWA core. Finally, an analysis of TMEM16A structures suggests residues likely to mediate interaction with CLCA1 VWA.

PubMed: 31995732
DOI: 10.1016/j.celrep.2019.12.059

Experimental method

X-RAY DIFFRACTION (2.6 Å)