Disulfide-Dependent Multimeric Assembly of Resistin Family Hormones

Abstract

Resistin, founding member of the resistin-like molecule (RELM) hormone family, is secreted selectively from adipocytes and induces liver-specific antagonism of insulin action, thus providing a potential molecular link between obesity and diabetes. Crystal structures of resistin and RELMbeta reveal an unusual multimeric structure. Each protomer comprises a carboxy-terminal disulfide-rich beta-sandwich "head" domain and an amino-terminal alpha-helical "tail" segment. The alpha-helical segments associate to form three-stranded coiled coils, and surface-exposed interchain disulfide linkages mediate the formation of tail-to-tail hexamers. Analysis of serum samples shows that resistin circulates in two distinct assembly states, likely corresponding to hexamers and trimers. Infusion of a resistin mutant, lacking the intertrimer disulfide bonds, in pancreatic-insulin clamp studies reveals substantially more potent effects on hepatic insulin sensitivity than those observed with wild-type resistin. This result suggests that processing of the intertrimer disulfide bonds may reflect an obligatory step toward activation.

Serum concentrations of resistin-like molecules β and γ are elevated in high-fat-fed and obese db/db mice, with increased production in the intestinal tract and bone marrow

“…RELMβ mRNA and protein were abundant in the colon, and to a lesser extent in the ileum. On the other hand, RELMγ mRNA was abundant in the colon, ileum, bone marrow, spleen, pancreas and fat, consistent with previous reports [18][19][20] (Fig. 2a, lower panel).…”

“…The Cterminus of RELMγ is highly homologous (84%) with RELMβ. Recently, the crystal structures of resistin and RELMβ were revealed to have a unique multimeric structure [20]. Each protomer is comprised of a 'head' and 'tail' segment and circulates as an assembly of hexamers and trimers, which reflect activation of resistin.…”

A sticky end for gastrointestinal helminths; the role of the mucus barrier

“…However, proteins with a structural, antimicrobial and regulatory function have been associated with the mucus gel and have been identified to be present during parasitic infection 87, 88, 89, 90, 91. Several nonmucin proteins have also been demonstrated to be present within goblet cell granules within the intestine, including IgG Fc‐gamma‐binding protein (FCGBP), trefoil factor (TTF), chloride channel regulator calcium‐activated‐1 (CLCA1), resistin‐like molecule (RELM)‐β and ZG16,87, 92, 93, 94 but relatively few have been investigated during GI nematode infection.…”

“…RELM‐β is found within ceacal and colonic mucus as a hexamer and trimer and is induced by a Th2 response 94. It has been proposed that RELM‐β can affect the ATP levels and hence the fitness of H. polygyrus and N. brasiliensis through impairing the parasites ability to feed.…”

The role of resistin as a regulator of inflammation: Implications for various human pathologies

“…In the mouse, resistin circulates in two forms: a high-molecular weight (HMW) form that is identical to the disulfide-linked hexamer and a low-molecular weight (LMW) form that represents a smaller trimer complex that is unable to form intertrimer disulfide bonds [13]. The LMW monomeric form in mice is considered to be more bioactive and potent in terms of hepatic insulin action impairment.…”