1fyh
From Proteopedia
1:1 COMPLEX BETWEEN AN INTERFERON GAMMA SINGLE-CHAIN VARIANT AND ITS RECEPTOR
Structural highlights
Disease[IFNG_HUMAN] In Caucasians, genetic variation in IFNG is associated with the risk of aplastic anemia (AA) [MIM:609135]. AA is a rare disease in which the reduction of the circulating blood cells results from damage to the stem cell pool in bone marrow. In most patients, the stem cell lesion is caused by an autoimmune attack. T-lymphocytes, activated by an endogenous or exogenous, and most often unknown antigenic stimulus, secrete cytokines, including IFN-gamma, which would in turn be able to suppress hematopoiesis. [INGR1_HUMAN] Defects in IFNGR1 are a cause of Mendelian susceptibility to mycobacterial disease (MSMD) [MIM:209950]; also known as familial disseminated atypical mycobacterial infection. This rare condition confers predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine and environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. The pathogenic mechanism underlying MSMD is the impairment of interferon-gamma mediated immunity whose severity determines the clinical outcome. Some patients die of overwhelming mycobacterial disease with lepromatous-like lesions in early childhood, whereas others develop, later in life, disseminated but curable infections with tuberculoid granulomas. MSMD is a genetically heterogeneous disease with autosomal recessive, autosomal dominant or X-linked inheritance.[1] [2] Function[IFNG_HUMAN] Produced by lymphocytes activated by specific antigens or mitogens. IFN-gamma, in addition to having antiviral activity, has important immunoregulatory functions. It is a potent activator of macrophages, it has antiproliferative effects on transformed cells and it can potentiate the antiviral and antitumor effects of the type I interferons. [INGR1_HUMAN] Receptor for interferon gamma. Two receptors bind one interferon gamma dimer. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBACKGROUND: Interferon-gamma (IFN-gamma) is a homodimeric cytokine that exerts its various activities by inducing the aggregation of two different receptors. The alpha chain receptor (IFN-gammaRalpha) is a high affinity receptor that binds to IFN-gamma in a symmetric bivalent manner to form a stable, intermediate 1:2 complex. This intermediate forms a binding template for the subsequent binding of two copies of the second receptor, beta chain receptor (IFN-gammaRbeta), producing the active 1:2:2 signaling complex. RESULTS: A single chain monovalent variant of IFN-gamma (scIFN-gamma) was constructed and complexed to one copy of the extracellular domain (ECD) of IFN-gammaRalpha. The structure of this 1:1 complex was determined and the hormone-receptor interface shown to be characterized by a number of hydrophilic interactions mediated by several highly ordered water networks. The scIFN-gamma interface consists of segments from each of the monomer chains of the homodimer. The principal hydrophobic contact of the receptor involves a tripeptide segment of the receptor having an unusual and high energy conformation. Despite containing only one binding site for IFN-gammaRalpha, the monovalent scIFN-gamma molecule has significant activity in antiviral biological assays. CONCLUSIONS: ScIFN-gamma binds the ECD of IFN-gammaRalpha through a highly hydrated interface with an important set of hormone-receptor contacts mediated through structured waters. Although the interface is highly hydrated, it supports tight binding and has a considerable degree of specificity. The biological activity of scIFN-gamma confirms that the scIFN-gamma:IFN-gammaRalpha complex represents a productive intermediate and that it can effectively recruit the other required component, IFN-gammaRbeta, to signal based on the 1:1:1 complex. The structure and activity of a monomeric interferon-gamma:alpha-chain receptor signaling complex.,Randal M, Kossiakoff AA Structure. 2001 Feb 7;9(2):155-63. PMID:11250200[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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