Myopathy-associated alphaB-crystallin mutants: abnormal phosphorylation, intracellular location, and interactions with other small heat shock proteins.

Three mutations (R120G, Q151X, and 464delCT) in the small heat shock protein alphaB-crystallin cause inherited myofibrillar myopathy. In an effort to elucidate the molecular basis for the associated myopathy, we have determined the following for these mutant alphaB-crystallin proteins: (i) the formation of aggregates in transfected cells; (ii) the partition into different subcellular fractions; (iii) the phosphorylation status; and (iv) the ability to interact with themselves, with wild-typealphaB-crystallin, and with other small heat shock proteins that are abundant in muscles. We found that all three alphaB-crystallin mutants have an increased tendency to form cytoplasmic aggregates in transfected cells and significantly increased levels of phosphorylation when compared with the wild-type protein. Although wild-type alphaB-crystallin partitioned essentially into the cytosol and membranes/organelles fractions, mutant alphaB-crystallin proteins partitioned additionally into the nuclear and cytoskeletal fractions. By using various protein interaction assays, including quantitative fluorescence resonance energy transfer measurements in live cells, we found abnormal interactions of the various alphaB-crystallin mutants with wild-type alphaB-crystallin, with themselves, and with the other small heat shock proteins Hsp20, Hsp22, and possibly with Hsp27. The collected data suggest that eachalphaB-crystallin mutant has a unique pattern of abnormal interaction properties. These distinct properties of the alphaB-crystallin mutants identified are likely to contribute to a better understanding of the gradual manifestation and clinical heterogeneity of the associated myopathy in patients.
AuthorsStephanie Simon, Jean-Marc Fontaine, Jody L Martin, Xiankui Sun, Adam D Hoppe, Michael J Welsh, Rainer Benndorf, Patrick Vicart
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 47 Pg. 34276-87 (Nov 23 2007) ISSN: 0021-9258 [Print] United States
PMID17897943 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Heat-Shock Proteins, Small
  • alpha-Crystallin B Chain
  • Animals
  • COS Cells
  • Cell Nucleus (metabolism, pathology)
  • Cercopithecus aethiops
  • Cytosol (metabolism, pathology)
  • Heat-Shock Proteins, Small (metabolism)
  • Humans
  • Muscular Diseases (genetics, metabolism, pathology)
  • Mutation
  • Phosphorylation
  • Protein Binding (genetics)
  • Rats
  • Transfection
  • alpha-Crystallin B Chain (genetics, metabolism)

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