COOH-terminal amino acids of the alpha subunit play common and different roles in human choriogonadotropin and follitropin

Yoo, Jakyoung; Zeng, Huawei; Ji, Inhae; Murdoch, William J.; Ji, Tae H.

doi:10.1016/s0021-9258(19)38615-6

Cited by 60 publications

(9 citation statements)

References 34 publications

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“…This high affinity site is, however, incapable of activating the receptors (19). There is a low affinity site in the membrane-associated C-terminal half of the LH/CG receptor, and it alone is capable of activating the receptor to induce hormone action (19)(20)(21)(22).…”

Section: Resultsmentioning

confidence: 99%

“…The high affinity site is in the extracellular N-terminal half (17)(18)(19), and the low affinity site is in the membrane-associated C-terminal half (20). The low affinity site alone is capable of activating the LH/CG receptor to induce hormone action (19)(20)(21)(22). The TSH receptor also has the high affinity hormone contact site in the N-terminal half (23,24), which appears to consist of multiple hormone contact points (25,26).…”

mentioning

confidence: 99%

“…For instance, the aC-terminal residues of FSH and hCG play crucial roles for receptor activation but in hormone-specific manners (30). Furthermore, a synthetic peptide corresponding to the C-terminal amino acids 83-92 of the a subunit is capable of binding to and activating the LH/CG receptor (21). However, it does not bind to the FSH receptor.…”

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confidence: 99%

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Differential Roles of Exoloop 1 of the Human Follicle-stimulating Hormone Receptor in Hormone Binding and Receptor Activation

1995

Journal of Biological Chemistry

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The follicle-stimulating hormone (FSH) receptor is a member of the glycoprotein hormone receptor subfamily of the seven-transmembrane receptor superfamily. These receptors have an extracellular N-terminal half of approximately 350 amino acids and a membrane-associated C-terminal half of approximately 350 amino acids. The N-terminal halves have the high affinity hormone binding site. On the other hand, the C-terminal half of the lutropin/choriogonadotropin receptor has the receptor activation site. However, little is known about the activation site and mechanism of the FSH receptor, although the existing evidence indicates crucial differences in the activation of the FSH receptor and the lutropin/choriogonadotropin receptor. As a first step to resolve this issue, we examined the upstream juxtamembrane five amino acids, Asp405-Ile406-His407-Thr408-Lys409, of the exoloop 1. Ala scan and multi-substitutions show that the five amino acid sequence is important for both hormone binding and receptor activation to induce cAMP synthesis, despite its short length. Specifically, His407 is important for high affinity hormone binding, whereas Asp405, Thr408, and Lys409 are crucial for receptor activation. The data suggest that the five amino acids may form a turn of helix that is an extension of the transmembrane helix 2. In this helical arrangement, Asp405, Thr408, and Lys409 are grouped to form a hydrophilic face of the helix, suggesting a correlation between this arrangement and receptor activation. In addition, the diverse and differential roles of the five amino acids indicate that high affinity hormone binding and receptor activation are discernible functions. These novel observations will be helpful for understanding the activation mechanism of the FSH receptor.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Differential Roles of Exoloop 1 of the Human Follicle-stimulating Hormone Receptor in Hormone Binding and Receptor Activation

1995

Journal of Biological Chemistry

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“…Photoaffinity labeling studies demonstrated that both ␣ and ␤ subunits affinity-labeled the LH/CG receptor (2). The truncation or substitution of hCG␣ C-terminal amino acid residues reduces the receptor-binding affinity and abolishes cAMP induction (3)(4)(5)(6). This is consistent with the observation that a dodecamer peptide corresponding to the hCG␣ C-terminal region, ␣ 81-92 , inhibited 125 I-hCG binding to the receptor (7) and that a decamer peptide, ␣ 83-92 , was capable of binding to cells possessing the LH/CG receptor and inducing cAMP synthesis (6).…”

mentioning

confidence: 99%

“…The truncation or substitution of hCG␣ C-terminal amino acid residues reduces the receptor-binding affinity and abolishes cAMP induction (3)(4)(5)(6). This is consistent with the observation that a dodecamer peptide corresponding to the hCG␣ C-terminal region, ␣ 81-92 , inhibited 125 I-hCG binding to the receptor (7) and that a decamer peptide, ␣ 83-92 , was capable of binding to cells possessing the LH/CG receptor and inducing cAMP synthesis (6). Also, the crystal structure of HF treated hCG suggests the ␣C-terminal region as part of the potential receptor binding site (8,9).…”

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confidence: 99%

Photoaffinity Labeling of the Lutropin Receptor with Synthetic Peptide for Carboxyl Terminus of the Human Choriogonadotropin γ Subunit

Kundu

McCormick

et al. 1996

Journal of Biological Chemistry

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Human choriogonadotropin (hCG) consists of an alpha subunit and a beta subunit. The existing evidence from various studies using truncation, substitution, synthetic hormone peptides, and hCG crystals suggests that the C-terminal region of the alpha subunit contacts the luteinizing hormone/choriogonoadotropin (LH/CG) receptor and is involved in receptor activation. Despite a deluge of the speculation and the important role of the alpha C-terminal region, direct evidence for its interaction with the receptor has been elusive. Because of the significant biological activity, it is imperative to prove the interaction of the alpha C-terminal region. For this purpose, decamer peptides corresponding to the alpha subunit sequence from His83 to Ser92 (alpha 83-92) were derivatized with the N-hydroxysuccinimide ester of 4-azidobenzoylglycine (ABG) and radioiodinated. The resulting ABG-125I-alpha 83-92 was capable of binding and activating the LH/CG receptor. Furthermore, UV-sensitive ABG-125I-alpha 83-92 exclusively photoaffinity-labeled an approximately of 86-kDa molecule. This labeled molecule was shown to be the LH/CG receptor by various methods including immunoprecipitation by anti-LH/CG receptor antiserum. In addition, evidence is presented that the amino group of alpha Lys91 of alpha 83-92 is in such close proximity to a carboxyl group of the receptor that this pair is cross-linked to form an amide, a zero length cross-link. This low affinity contact of alpha 83-92 and the receptor is sufficient for receptor activation and is crucial for the full understanding of the mechanistics of the receptor activation steps.

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Molecular architecture and biorecognition processes of the cystine knot protein superfamily: part I. The glycoprotein hormones

2000

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COOH-terminal amino acids of the alpha subunit play common and different roles in human choriogonadotropin and follitropin

Cited by 60 publications

References 34 publications

Differential Roles of Exoloop 1 of the Human Follicle-stimulating Hormone Receptor in Hormone Binding and Receptor Activation

Differential Roles of Exoloop 1 of the Human Follicle-stimulating Hormone Receptor in Hormone Binding and Receptor Activation

Photoaffinity Labeling of the Lutropin Receptor with Synthetic Peptide for Carboxyl Terminus of the Human Choriogonadotropin γ Subunit

Molecular architecture and biorecognition processes of the cystine knot protein superfamily: part I. The glycoprotein hormones

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