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Department of Chemistry (K.M.F.) Union College Schenectady,
New York 12308
Division of Molecular Medicine (K.M.F.,
J.A.D., P.V.R.) Wadsworth Center Albany, New York
12201-0509
The crystal structure of a ßThr26Ala mutant of
human follicle-stimulating hormone (hFSH) has been determined to 3.0 Å
resolution. The hFSH mutant was expressed in baculovirus-infected Hi5
insect cells and purified by affinity chromatography, using a
ßhFSH-specific monoclonal antibody. The ßThr26Ala mutation
results in elimination of the ßAsn24 glycosylation site, yielding
protein more suitable for crystallization without affecting the
receptor binding and signal transduction activity of the glycohormone.
The crystal structure has two independent hFSH molecules in the
asymmetric unit and a solvent content of about 80%. The 
- and
ßsubunits of hFSH have similar folds, consisting of central
cystine-knot motifs from which three ß-hairpins extend. The two
subunits associate very tightly in a head-to-tail arrangement, forming
an elongated, slightly curved structure, similar to that of human
chorionic gonadotropin (hCG). The hFSH heterodimers differ only in the
conformations of the amino and carboxy termini and the second loop of
the ß-subunit (L2ß). Detailed comparison of the structures of hFSH
and hCG reveals several differences in the ß-subunits that may be
important with respect to receptor binding specificity or signal
transduction. These differences include conformational changes and/or
differential distributions of polar or charged residues in loops L3ß
(hFSH residues 62–73), the cystine noose, or determinant loop
(residues 87–94), and the carboxy-terminal loop (residues 94–104). An
additional interesting feature of the hFSH structure is an extensive
hydrophobic patch in the area formed by loops L1, L3, and ßL2.
Glycosylation at Asn52 is well known to be required for full signal
transduction activity and heterodimer stability. The structure reveals
an intersubunit hydrogen bonding interaction between this carbohydrate
and ßTyr58, an indication of a mechanism by which the carbohydrate
may stabilize the heterodimer.
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