| Structural highlights
Function
CLCA1_HUMAN May be involved in mediating calcium-activated chloride conductance. May play critical roles in goblet cell metaplasia, mucus hypersecretion, cystic fibrosis and AHR. May be involved in the regulation of mucus production and/or secretion by goblet cells. Involved in the regulation of tissue inflammation in the innate immune response. May play a role as a tumor suppressor. Induces MUC5AC.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
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-A crystal structure of human CLCA1 VWA bound to Ca(2+). 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 alpha3 and alpha4 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(2+) over Ca(2+) and that alpha6 atypically extends from the VWA core. Finally, an analysis of TMEM16A structures suggests residues likely to mediate interaction with CLCA1 VWA.
Structural and Biophysical Analysis of the CLCA1 VWA Domain Suggests Mode of TMEM16A Engagement.,Berry KN, Brett TJ Cell Rep. 2020 Jan 28;30(4):1141-1151.e3. doi: 10.1016/j.celrep.2019.12.059. Epub, 2020 Jan 28. PMID:31995732[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bustin SA, Li SR, Dorudi S. Expression of the Ca2+-activated chloride channel genes CLCA1 and CLCA2 is downregulated in human colorectal cancer. DNA Cell Biol. 2001 Jun;20(6):331-8. PMID:11445004 doi:10.1089/10445490152122442
- ↑ Toda M, Tulic MK, Levitt RC, Hamid Q. A calcium-activated chloride channel (HCLCA1) is strongly related to IL-9 expression and mucus production in bronchial epithelium of patients with asthma. J Allergy Clin Immunol. 2002 Feb;109(2):246-50. PMID:11842292 doi:10.1067/mai.2002.121555
- ↑ Hoshino M, Morita S, Iwashita H, Sagiya Y, Nagi T, Nakanishi A, Ashida Y, Nishimura O, Fujisawa Y, Fujino M. Increased expression of the human Ca2+-activated Cl the asthmatic airway. Am J Respir Crit Care Med. 2002 Apr 15;165(8):1132-6. PMID:11956057 doi:10.1164/ajrccm.165.8.2107068
- ↑ Yurtsever Z, Sala-Rabanal M, Randolph DT, Scheaffer SM, Roswit WT, Alevy YG, Patel AC, Heier RF, Romero AG, Nichols CG, Holtzman MJ, Brett TJ. Self-cleavage of human CLCA1 protein by a novel internal metalloprotease domain controls calcium-activated chloride channel activation. J Biol Chem. 2012 Dec 7;287(50):42138-49. PMID:23112050 doi:10.1074/jbc.M112.410282
- ↑ Gruber AD, Elble RC, Ji HL, Schreur KD, Fuller CM, Pauli BU. Genomic cloning, molecular characterization, and functional analysis of human Genomics. 1998 Dec 1;54(2):200-14. PMID:9828122 doi:10.1006/geno.1998.5562
- ↑ Berry KN, Brett TJ. Structural and Biophysical Analysis of the CLCA1 VWA Domain Suggests Mode of TMEM16A Engagement. Cell Rep. 2020 Jan 28;30(4):1141-1151.e3. doi: 10.1016/j.celrep.2019.12.059. Epub, 2020 Jan 28. PMID:31995732 doi:http://dx.doi.org/10.1016/j.celrep.2019.12.059
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