Abstract
Adiponectin 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 domain receptors, AdipoR1 and AdipoR2, as well as to 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.
Highlights
Adiponectin is a highly abundant protein hormone secreted by adipose tissue
Adiponectin is the most abundant adipokine produced exclusively by adipocytes, and it accounts for 0.01% of total plasma proteins, with a serum concentration ranging from 5–30 g/ml [1]
Structural metal ions in adiponectin are important for Tcadherin binding Full-length adiponectin is a large and heavily posttranslationally modified protein, features that do not favor crystallization; we decided to first focus our attention on the globular domain, which lacks these modifications
Summary
Adiponectin 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 has been reported to bind to two seven-transmembrane domain receptors, AdipoR1 and AdipoR2, as well as to the protein T-cadherin, which is highly expressed in the cardiovascular system and binds only the high-molecular-weight form of adiponectin. The first two are members of a class of seven-transmembrane domain receptors called the progesterone and AdipoQ receptor superfamily [20] and are structurally and functionally unrelated to G protein– coupled receptors [21] Their expression and their biological activity vary among different tissues, with AdipoR1 being mostly expressed in skeletal muscle, heart, kidney, and liver, whereas AdipoR2 is expressed almost exclusively in the liver [22, 23]. We investigate adiponectin–T-cadherin interactions using a combination of biochemical approaches and protein engineering
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