| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
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.
This article has been cited by other articles:
 |
|
 |
|
  C. Galet, F. Guillou, F. Foulon-Gauze, Y. Combarnous, and M. Chopineau The {beta}104-109 sequence is essential for the secretion of correctly folded single-chain {beta}{alpha} horse LH/CG and for its FSH activity J. Endocrinol., October 1, 2009; 203(1): 167 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Nunez Miguel, J Sanders, D Y Chirgadze, J Furmaniak, and B Rees Smith Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein-protein interactions J. Mol. Endocrinol., May 1, 2009; 42(5): 381 - 395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R Nunez Miguel, J Sanders, D Y Chirgadze, T L Blundell, J Furmaniak, and B Rees Smith FSH and TSH binding to their respective receptors: similarities, differences and implication for glycoprotein hormone specificity J. Mol. Endocrinol., September 1, 2008; 41(3): 145 - 164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ghadami, S.A. Salama, N. Khatoon, R. Chilvers, M. Nagamani, P.J. Chedrese, and A. Al-Hendy Toward gene therapy of primary ovarian failure: adenovirus expressing human FSH receptor corrects the Finnish C566T mutation Mol. Hum. Reprod., January 1, 2008; 14(1): 9 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Jablonka-Shariff, T. R. Kumar, J. Eklund, A. Comstock, and I. Boime Single-Chain, Triple-Domain Gonadotropin Analogs with Disulfide Bond Mutations in the {alpha}-Subunit Elicit Dual Follitropin and Lutropin Activities in Vivo Mol. Endocrinol., June 1, 2006; 20(6): 1437 - 1446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Okada, J. L. Ellsworth, D. M. Durnam, H. S. Haugen, J. L. Holloway, M. L. Kelley, K. E. Lewis, H. Ren, P. O. Sheppard, H. M. Storey, et al. A Glycoprotein Hormone Expressed in Corticotrophs Exhibits Unique Binding Properties on Thyroid-Stimulating Hormone Receptor Mol. Endocrinol., February 1, 2006; 20(2): 414 - 425. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P N Themmen An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms Reproduction, September 1, 2005; 130(3): 263 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.C. Low, S.L. Nunes, A.J. Bitonti, and J.A. Dumont Oral and pulmonary delivery of FSH-Fc fusion proteins via neonatal Fc receptor-mediated transcytosis Hum. Reprod., July 1, 2005; 20(7): 1805 - 1813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Legardinier, M. Duonor-Cerutti, G. Devauchelle, Y. Combarnous, and C. Cahoreau Biological activities of recombinant equine luteinizing hormone/chorionic gonadotropin (eLH/CG) expressed in Sf9 and Mimic insect cell lines J. Mol. Endocrinol., February 1, 2005; 34(1): 47 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Kleinau, H. Jaschke, S. Neumann, J. Lattig, R. Paschke, and G. Krause Identification of a Novel Epitope in the Thyroid-stimulating Hormone Receptor Ectodomain Acting as Intramolecular Signaling Interface J. Biol. Chem., December 3, 2004; 279(49): 51590 - 51600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xing, W. Lin, M. Jiang, D. Cao, R. V. Myers, M. P. Bernard, and W. R. Moyle Use of Protein Knobs to Characterize the Position of Conserved {alpha}-Subunit Regions in Lutropin Receptor Complexes J. Biol. Chem., October 22, 2004; 279(43): 44427 - 44437. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Bernard, W. Lin, D. Cao, R. V. Myers, Y. Xing, and W. R. Moyle Only a Portion of the Small Seatbelt Loop in Human Choriogonadotropin Appears Capable of Contacting the Lutropin Receptor J. Biol. Chem., October 22, 2004; 279(43): 44438 - 44441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xing, R. V. Myers, D. Cao, W. Lin, M. Jiang, M. P. Bernard, and W. R. Moyle Glycoprotein Hormone Assembly in the Endoplasmic Reticulum: I. THE GLYCOSYLATED END OF HUMAN {alpha}-SUBUNIT LOOP 2 IS THREADED THROUGH A {beta}-SUBUNIT HOLE J. Biol. Chem., August 20, 2004; 279(34): 35426 - 35436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xing, R. V. Myers, D. Cao, W. Lin, M. Jiang, M. P. Bernard, and W. R. Moyle Glycoprotein Hormone Assembly in the Endoplasmic Reticulum: II. MULTIPLE ROLES OF A REDOX SENSITIVE {beta}-SUBUNIT DISULFIDE SWITCH J. Biol. Chem., August 20, 2004; 279(34): 35437 - 35448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xing, R. V. Myers, D. Cao, W. Lin, M. Jiang, M. P. Bernard, and W. R. Moyle Glycoprotein Hormone Assembly in the Endoplasmic Reticulum: III. THE SEATBELT AND ITS LATCH SITE DETERMINE THE ASSEMBLY PATHWAY J. Biol. Chem., August 20, 2004; 279(34): 35449 - 35457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xing, R. V. Myers, D. Cao, W. Lin, M. Jiang, M. P. Bernard, and W. R. Moyle Glycoprotein Hormone Assembly in the Endoplasmic Reticulum: IV. PROBABLE MECHANISM OF SUBUNIT DOCKING AND COMPLETION OF ASSEMBLY J. Biol. Chem., August 20, 2004; 279(34): 35458 - 35468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Jablonka-Shariff and I. Boime Luteinizing Hormone and Follicle-Stimulating Hormone Exhibit Different Secretion Patterns from Cultured Madin-Darby Canine Kidney Cells Biol Reprod, March 1, 2004; 70(3): 649 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sohn, H. Youn, M. Jeoung, Y. Koo, C. Yi, I. Ji, and T. H. Ji Orientation of Follicle-stimulating Hormone (FSH) Subunits Complexed with the FSH Receptor: {beta} SUBUNIT TOWARD THE N TERMINUS OF EXODOMAIN AND {alpha} SUBUNIT TO EXOLOOP 3 J. Biol. Chem., November 28, 2003; 278(48): 47868 - 47876. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. D. Cohen, J. T. Bariteau, L. M. Magenis, and J. A. Dias Regulation of Follitropin Receptor Cell Surface Residency by the Ubiquitin-Proteasome Pathway Endocrinology, October 1, 2003; 144(10): 4393 - 4402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ulloa-Aguirre, C. Timossi, J. Barrios-de-Tomasi, A. Maldonado, and P. Nayudu Impact of Carbohydrate Heterogeneity in Function of Follicle-Stimulating Hormone: Studies Derived from in Vitro and in Vivo Models Biol Reprod, August 1, 2003; 69(2): 379 - 389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Perlman, B. van den Hazel, J. Christiansen, S. Gram-Nielsen, C. B. Jeppesen, K. V. Andersen, T. Halkier, S. Okkels, and H. T. Schambye Glycosylation of an N-Terminal Extension Prolongs the Half-Life and Increases the in Vivo Activity of Follicle Stimulating Hormone J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3227 - 3235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. B. Fralish, B. Dattilo, and D. Puett Structural Analysis of Yoked Chorionic Gonadotropin-Luteinizing Hormone Receptor Ectodomain Complexes by Circular Dichroic Spectroscopy Mol. Endocrinol., July 1, 2003; 17(7): 1192 - 1202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. B. Fralish, P. Narayan, and D. Puett Consequences of Single-Chain Translation on the Structures of Two Chorionic Gonadotropin Yoked Analogs in {alpha}-{beta} and {beta}-{alpha} Configurations Mol. Endocrinol., April 1, 2003; 17(4): 757 - 767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Schubert, P. Narayan, and D. Puett Specificity of Cognate Ligand-Receptor Interactions: Fusion Proteins of Human Chorionic Gonadotropin and the Heptahelical Receptors for Human Luteinizing Hormone, Thyroid-Stimulating Hormone, and Follicle-Stimulating Hormone Endocrinology, January 1, 2003; 144(1): 129 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Garcia-Campayo, T. R. Kumar, and I. Boime Thyrotropin, Follitropin, and Chorionic Gonadotropin Expressed as a Single Multifunctional Unit Reveal Remarkable Permissiveness in Receptor-Ligand Interactions Endocrinology, October 1, 2002; 143(10): 3773 - 3778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. C. Layman, A. L. A. Porto, J. Xie, L. A. C. R. da Motta, L. D. C. da Motta, W. Weiser, and P. M. Sluss FSH{beta} Gene Mutations in a Female with Partial Breast Development and a Male Sibling with Normal Puberty and Azoospermia J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3702 - 3707. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Smits, C. Govaerts, I. Nubourgh, L. Pardo, G. Vassart, and S. Costagliola Lysine 183 and Glutamic Acid 157 of the TSH Receptor: Two Interacting Residues with a Key Role in Determining Specificity toward TSH and Human CG Mol. Endocrinol., April 1, 2002; 16(4): 722 - 735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Vlaeminck-Guillem, S.-C. Ho, P. Rodien, G. Vassart, and S. Costagliola Activation of the cAMP Pathway by the TSH Receptor Involves Switching of the Ectodomain from a Tethered Inverse Agonist to an Agonist Mol. Endocrinol., April 1, 2002; 16(4): 736 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J. Walton, V. T. Nguyen, V. Y. Butnev, V. Singh, W. T. Moore, and G. R. Bousfield Characterization of Human FSH Isoforms Reveals a Nonglycosylated {beta}-Subunit in Addition to the Conventional Glycosylated {beta}-Subunit J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3675 - 3685. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schmidt, R. MacColl, B. Lindau-Shepard, D. R. Buckler, and J. A. Dias Hormone-induced Conformational Change of the Purified Soluble Hormone Binding Domain of Follitropin Receptor Complexed with Single Chain Follitropin J. Biol. Chem., June 22, 2001; 276(26): 23373 - 23381. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
