title: Abnormal small heat shock protein interactions involving neuropathy-associated HSP22 (HSPB8) mutants.
abstract: Two mutations (K141E, K141N) in the small heat shock protein (sHSP) HSP22 (HSPB8) are associated with the inherited peripheral motor neuron disorders distal hereditary motor neuropathy type II and axonal Charcot-Marie-Tooth disease type 2L. HSP22 is known to form homodimers, heterodimers with other sHSPs, and larger oligomers. In an effort to elucidate the cellular basis for these diseases, we have determined the ability of mutant HSP22 to interact with itself, with wild-type HSP22, and with other sHSPs that are abundant in neurons. Using the yeast two-hybrid method, quantitative fluorescence resonance energy transfer in live cells, and cross-linking, we found aberrantly increased interactions of mutant HSP22 forms with themselves, with wild-type HSP22, and with the other sHSPs, alphaB-crystallin, and HSP27. Interaction with HSP20 was not affected by the mutations. The data suggest that each mutant form of HSP22 has a characteristic pattern of abnormal interaction properties. A mutation (S135F) in HSP27 that is also associated with these disorders showed increased interaction with wild-type HSP22 also, suggesting linkage of these two etiologic factors, HSP22 and HSP27, into one common pathway. Increased interactions involving mutant sHSPs may be the molecular basis for their increased tendency to form cytoplasmic protein aggregates, and for the occurrence of the associated neuropathies.
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, 109 Zina Pitcher Pl., Ann Arbor, MI 48109-2200, USA.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fontaine
authors.forename: Xiankui
authors.initials: X
authors.lastname: Sun
authors.forename: Adam D
authors.initials: AD
authors.lastname: Hoppe
authors.forename: Stephanie
authors.initials: S
authors.lastname: Simon
authors.forename: Patrick
authors.initials: P
authors.lastname: Vicart
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
authors.forename: Rainer
authors.initials: R
authors.lastname: Benndorf
mesh_terms: D000818:Animals; D002460:Cell Line; D002607:Charcot-Marie-Tooth Disease / Q000209:etiology* / Q000235:genetics; D019281:Dimerization; D050886:HSP20 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D050888:Heat-Shock Proteins, Small / Q000235:genetics / Q000378:metabolism*; D015417:Hereditary Sensory and Motor Neuropathy / Q000209:etiology / Q000235:genetics; D006801:Humans; D018832:Molecular Chaperones; D020125:Mutation, Missense; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D050886:HSP20 Heat-Shock Proteins; C494382:HSPB6 protein, human; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D050888:Heat-Shock Proteins, Small; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases