Parallel regulation of membrane trafficking and dominant-negative effects by misrouted gonadotropin-releasing hormone receptor mutants.
Gonadotropin-releasing hormone (GnRH) receptor mutants from patients with hypogonadotropic hypogonadism are frequently misrouted proteins that exert a dominant-negative (DN) effect on human (h) wild-type (WT) receptor, due to oligomerization and retention in the endoplasmic reticulum. Pharmacologic chaperones restore correct folding, rescuing mutants and WT receptor from this oligomer. Rat WT retains the ability to oligomerize (since human and mouse mutants exert a DN effect on rat (r) WT sequence) but, unlike human or mouse, escapes the DN effect of GnRH receptor (Gn-RHR) mutants because rGnRHR mutants route to the plasma membrane with higher efficiency than mouse or human mutants. These distinct behaviors of mouse and rat GnRHRs (distinguished by only four semi- or non-conservative amino acid differences) led us to assess the role of each amino acid. The difference in both routing and the DN effect appears mediated primarily by Ser(216) in the rGnRHR. The homologous amino acid in the hGn-RHR is also Ser and is compensated for by the primate-unique insertion of Lys(191) that, alone, dramatically decreases routing of the receptor. These studies establish the relation between the DN effect and altered receptor trafficking and explain why hGnRHR is more susceptible to defective trafficking by disease-related point mutations than rodent counterparts.
Knollman
Paul E
PE
Division of Neuroscience and Reproductive Biology, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006, USA.
Janovick
Jo Ann
JA
Brothers
Shaun P
SP
Conn
P Michael
PM
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D019143:Evolution, Molecular; D005799:Genes, Dominant; D006062:Gonadotropins / Q000378:metabolism*; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D017510:Protein Folding; D021381:Protein Transport; D051381:Rats; D011966:Receptors, LHRH / Q000235:genetics* / Q000502:physiology*; D012694:Serine / Q000737:chemistry; D014162:Transfection
D006062:Gonadotropins; D007295:Inositol Phosphates; D011966:Receptors, LHRH; D012694:Serine; D008239:Lysine