Redox-dependent structural ambivalence of the cytoplasmic domain in the inner ear-specific cadherin 23 isoform.
Cadherin 23 (Cdh23), an essential factor in inner ear mechano-electric transduction, exists in two alternatively spliced forms, Cdh23(+68) and Cdh23(-68), depending on the presence and absence of exon 68. Cdh23(+68) is inner ear-specific. The exon 68-corresponding region confers an alpha-helical configuration upon the cytoplasmic domain (Cy) and includes a cysteine residue, Cys(3240). We demonstrate here that Cy(+68) as well as the transmembrane (TM) plus Cy(+68) region is present in two different forms in transfected cells, reduced and non-reduced, the latter existing in more compact configuration than the former. The observed characteristic of Cy(+68) was completely abolished by Cys(3240)Ala substitution. Treatment of TMCy(+68)-transfected cells with diethyl maleate, a glutathione depleting reagent, resulted in conversion of the non-reduced to the reduced form of TMCy(+68), suggesting glutathione to be a Cys(3240)-binding partner. Multiple alignment of mammalian Cdh23Cy sequences indicated the occurrence of conformation-inducible Cys in Cdh23Cy of mammals, but not lower vertebrates. The implications of Cys-dependent structural ambivalence of Cdh23 in inner ear mechanosensation are discussed.
Department of Developmental Biology, Institute for Developmental Research, Aichi Human Service Center, Kasugai 480-0392, Japan.
Satoshi
S
Yonezawa
Atsuko
A
Hanai
Norihiro
N
Mutoh
Akihiko
A
Moriyama
Takashi
T
Kageyama
D000595:Amino Acid Sequence; D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D007758:Ear, Inner / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000648:ultrastructure; D017434:Protein Structure, Tertiary; D013045:Species Specificity; D013329:Structure-Activity Relationship
C442480:CDH23 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D020033:Protein Isoforms