Structural polymorphism visualized by electron of oligomeric adiponectin microscopy

Adiponectin, a macromolecular complex similar to the members of the C1q and other collagenous homologues, elicits diverse biological functions, including anti-diabetes, anti-atherosclerosis, anti-inflammation and antitumor activities, which have been directly linked to the high molecular weight (HMW) oligomeric structures formed by multiples of adiponectin trimers. Here, we report the 3-D reconstructions of isolated full-length, recombinant murine C39A adiponectin trimer and hexamer of wild-type trimers (the major HMW form) determined by single-particle analysis of electron micrographs. The pleiomorphic ensemble of collagen-like stretches of the trimers leads to a dynamic structure of HMW that partition into two major classes, the fan-shaped (class I) and bouquet-shaped (class II). In both of these, while the N termini cluster into a compact ellipsoid-shaped (similar to 60 angstrom x 45 angstrom x similar to 45 angstrom) volume, the collagenous domains assume a variety of arrangements. The domains are splayed by up to similar to 90 degrees in class I, can form a close-packed, up to similar to 100 x 40 A cylindrical assembly in class II, which can house about half of the 66 putative collagen-like sequence and the rest, tethered to the trimeric globular domains at the C terminus, are highly dynamic. As a result, the globular domains elaborate a variety of arrangements, covering an area of up to similar to 4.9 x 10(5) angstrom(2) and up to similar to 320 angstrom apart,some of which were captured in reconstructions of class II. Our reconstructions suggest that the N-terminal structured domain, agreeing approximately with the expected volume for the octadecameric assembly of the terminal 27 amino acids, is crucial to the formation of the functionally active HMW. On the other hand, conformational flexibility of the trimers at the C terminus can allow the HMW to access and cluster disparate target ligands binding to the globular domains, which may be necessary to activate cellular signaling leading to the remarkable functional diversity of adiponectin. (c) 2008 Elsevier Ltd. All rights reserved.