6u66
Structure of the trimeric globular domain of Adiponectin
Structural highlights
DiseaseADIPO_HUMAN The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. FunctionADIPO_HUMAN Important adipokine involved in the control of fat metabolism and insulin sensitivity, with direct anti-diabetic, anti-atherogenic and anti-inflammatory activities. Stimulates AMPK phosphorylation and activation in the liver and the skeletal muscle, enhancing glucose utilization and fatty-acid combustion. Antagonizes TNF-alpha by negatively regulating its expression in various tissues such as liver and macrophages, and also by counteracting its effects. Inhibits endothelial NF-kappa-B signaling through a cAMP-dependent pathway. May play a role in cell growth, angiogenesis and tissue remodeling by binding and sequestering various growth factors with distinct binding affinities, depending on the type of complex, LMW, MMW or HMW.[1] Publication Abstract from PubMedAdiponectin is a highly abundant protein hormone secreted by adipose tissue. It elicits diverse biological responses, including anti-diabetic, anti-inflammatory, anti-tumor and anti-atherosclerotic effects. Adiponectin consists of a globular domain and a collagen-like domain, and it occurs in three major oligomeric forms that self-assemble: trimers, hexamers, and high molecular weight oligomers. Adiponectin has been reported to bind to two seven-transmembrane domains receptors, AdipoR1 and AdipoR2, as well as the protein T-cadherin, which is highly expressed in the cardiovascular system and binds only the high molecular weight form of adiponectin. The molecular mechanisms underlying this specificity remain unclear. Here, we used a combination of X-ray crystallography and protein engineering to define the details of adiponectin's interaction with T-cadherin. We found that T-cadherin binds to the globular domain of adiponectin, relying on structural stabilization of this domain by bound metal ions. Moreover, we show that the adiponectin globular domain can be engineered to enhance its binding affinity for T-cadherin. These results help to define the molecular basis for the interaction between adiponectin and T-cadherin, and our engineered globular domain variants may be useful tools for further investigating adiponectin's functions. Mapping and engineering the interaction between adiponectin and T-cadherin.,Pascolutti R, Erlandson SC, Burri DJ, Zheng S, Kruse AC J Biol Chem. 2020 Jan 8. pii: RA119.010970. doi: 10.1074/jbc.RA119.010970. PMID:31915248[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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