Document Detail


Cytoplasmic amino acids within the membrane interface region influence connexin oligomerization.
MedLine Citation:
PMID:  22722762     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Gap junction channels composed of connexins connect cells, allowing intercellular communication. Their cellular assembly involves a unique quality-control pathway. Some connexins [including connexin43 (Cx43) and Cx46] oligomerize in the trans-Golgi network following export of stabilized monomers from the endoplasmic reticulum (ER). In contrast, other connexins (e.g., Cx32) oligomerize early in the secretory pathway. Amino acids near the cytoplasmic aspect of the third transmembrane domain have previously been shown to determine this difference in assembly sites. Here, we characterized the oligomerization of two connexins expressed prominently in the vasculature, Cx37 and Cx40, using constructs containing a C-terminal dilysine-based ER retention/retrieval signal (HKKSL) or treatment with brefeldin A to block ER vesicle trafficking. Both methods led to intracellular retention of connexins, since the cells lacked gap junction plaques. Retention of Cx40 in the ER prevented it from oligomerizing, comparable to Cx43. By contrast, ER-retained Cx37 was partially oligomerized. Replacement of two amino acids near the third transmembrane domain of Cx43 (L152 and R153) with the corresponding amino acids from Cx37 (M152 and G153) resulted in early oligomerization in the ER. Thus, residues that allow Cx37 to oligomerize early in the secretory pathway could restrict its interactions with coexpressed Cx40 or Cx43 by favoring homomeric oligomerization, providing a structural basis for cells to produce gap junction channels with different connexin composition.
Authors:
Tekla D Smith; Aditi Mohankumar; Peter J Minogue; Eric C Beyer; Viviana M Berthoud; Michael Koval
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-06-22
Journal Detail:
Title:  The Journal of membrane biology     Volume:  245     ISSN:  1432-1424     ISO Abbreviation:  J. Membr. Biol.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-07-23     Completed Date:  2012-12-14     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  0211301     Medline TA:  J Membr Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  221-30     Citation Subset:  IM    
Affiliation:
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Whitehead Biomedical Research Building, Atlanta, GA 30022, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acids / chemistry,  metabolism*
Cell Membrane / metabolism*
Connexin 43 / chemistry,  metabolism
Connexins / chemistry,  metabolism*
Cytosol / metabolism*
Fluorescent Antibody Technique
Gap Junctions / metabolism
Humans
Protein Multimerization
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
P50-AA013757/AA/NIAAA NIH HHS; R01 EY008368/EY/NEI NIH HHS; R01 HL059199/HL/NHLBI NIH HHS; R01-EY08368/EY/NEI NIH HHS; R01-HL083120/HL/NHLBI NIH HHS; R01-HL59199/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Amino Acids; 0/Connexin 43; 0/Connexins; 0/connexin 37
Comments/Corrections

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