Functional homodimeric glycoprotein hormones: implications for hormone action and evolution.
BACKGROUND
Human chorionic gonadotropin (hCG), lutropin, follitropin, and thyrotropin act as alpha beta heterodimers to control reproduction and thyroid function. The alpha and beta subunits of these proteins are divided into three loops (alpha 1,alpha 2,alpha 3; beta 1,beta 2,beta 3) by cysteine knots and the heterodimer is stabilized by 20 beta-subunit residues wrapped around alpha 2 like a seatbelt. Understanding how these hormones interact with their receptors, a matter of considerable dispute, would facilitate design of pro- and anti-fertility agents.


RESULTS
By swapping alpha 2 for beta 2 and vice versa and, in some cases, adding an amino-terminal coiled-coil dimerization domain, we prepared homodimeric analogs that have the conformation found in each 'half' of hCG. Homodimers containing loops beta 1,alpha 2,beta 3 and none, part, or all of the seatbelt stimulated signal transduction to the same extent as hCG, albeit with lower potency. Those containing alpha 1,beta 2,alpha 3 were inactive.


CONCLUSIONS
The activities of homodimers containing the beta 1,alpha 2,beta 3 groove exceed those of other minimized analogs more than 100-1000-fold, suggesting this portion of the hormone forms the major receptor contact. The discovery that glycoprotein hormone heterodimers can be converted to functional homodimers supports the proposal that this protein family evolved from an active homodimeric ancestor by gene duplication and acquisition of mutations to loop 2 that prevent homodimerization. This approach to protein minimization should be applicable to other proteins composed of architecturally related subunits, including those that might have arisen by gene duplication.
Moyle
W R
WR
Department of Obstetrics and Gynecology, Robert Wood Johnson (Rutgers) Medical School, Piscataway, NJ 08854, USA.
Myers
R V
RV
Wang
Y
Y
Han
Y
Y
Lin
W
W
Kelley
G L
GL
Ehrlich
P H
PH
Rao
S N
SN
Bernard
M P
MP
D000595:Amino Acid Sequence; D000818:Animals; D006063:Chorionic Gonadotropin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D019281:Dimerization; D019143:Evolution, Molecular; D005640:Follicle Stimulating Hormone / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007986:Luteinizing Hormone / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000502:physiology; D012098:Reproduction / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D013972:Thyrotropin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
D006063:Chorionic Gonadotropin; D011956:Receptors, Cell Surface; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D013972:Thyrotropin