PDBsum entry: 1y7j

Signaling protein

PDB id: 1y7j

Contents

Protein chain

40 a.a. *

* Residue conservation analysis

PDB id:

1y7j

Name:

Signaling protein

Title:

Nmr structure family of human agouti signalling protein (80- 132: q115y, s124y)

Structure:

Agouti signaling protein. Chain: a. Fragment: residies 80-132. Synonym: agouti switch protein. Engineered: yes. Mutation: yes

Source:

Synthetic: yes. Other_details: sequence occurs naturally in humans, genes asip, agti, agtil, asp

NMR struc:

21 models

Authors:

J.C.Mcnulty,P.J.Jackson,D.A.Thompson,B.Chai,I.Gantz, G.S.Barsh,P.E.Dawson,G.L.Millhauser

Key ref:

J.C.McNulty et al. (2005). Structures of the agouti signaling protein. J Mol Biol, 346, 1059-1070. PubMed id: 15701517 DOI: 10.1016/j.jmb.2004.12.030

Date:

08-Dec-04 Release date: 15-Feb-05

Protein chain

P42127  (ASIP_HUMAN) -  Agouti-signaling protein

Seq: 132 a.a.

Struc: 40 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 

• Cellular component: extracellular region (1 term)
• Biological process: hormone-mediated signaling (1 term)

DOI no: 10.1016/j.jmb.2004.12.030

J Mol Biol 346:1059-1070 (2005)

PubMed id: 15701517

Structures of the agouti signaling protein.

J.C.McNulty, P.J.Jackson, D.A.Thompson, B.Chai, I.Gantz, G.S.Barsh, P.E.Dawson, G.L.Millhauser.

ABSTRACT

Expression of the agouti signaling protein (ASIP) during hair growth produces the red/yellow pigment pheomelanin. ASIP, and its neuropeptide homolog the agouti-related protein (AgRP) involved in energy balance, are novel, paracrine signaling molecules that act as inverse agonists at distinct subsets of melanocortin receptors. Ubiquitous ASIP expression in mice gives rise to a pleiotropic phenotype characterized by a uniform yellow coat color, obesity, overgrowth, and metabolic derangements similar to type II diabetes in humans. Here we report the synthesis and NMR structure of ASIP's active, cysteine-rich, C-terminal domain. ASIP adopts the inhibitor cystine knot fold and, along with AgRP, are the only known mammalian proteins in this structure class. Moreover, ASIP populates two distinct conformers resulting from a cis peptide bond at Pro102-Pro103 and a coexistence of cis/trans isomers of Ala104-Pro105. Pharmacologic studies of Pro-->Ala mutants demonstrate that the minor conformation with two cis peptide bonds is responsible for activity at all MCRs. The loop containing the heterogeneous Ala-Pro peptide bond is conserved in mammals, and suggests that ASIP is either trapped by evolution in this unusual configuration or possesses function outside of strict MCR antagonism.

Selected figure(s)

Figure 3.
Figure 3. (a) Summary of backbone-backbone NOEs (arrows) and HX protection (thick lines between NH donors and CO acceptors) in the b-sheet region. (b) Sausage diagrams obtained from the 20 lowest energy structures for both cis ASIP-YY and trans ASIP-YY.

Figure 4.
Figure 4. Structure of ASIP-YY. Ribbon diagrams of cis (a), and trans ASIP-YY (b). For clarity, cysteine residues involved in disulfide bonds are labeled in the cis ASIP-YY structure and relevant loops are labeled in the trans ASIP-YY structure. Also noted is the threading disulfide indicative of the ICK fold motif. In (c), cis and trans ASIP-YY are shown superimposed with their b-sheets aligned. The persistent cis Pro102-Pro103 peptide bond and the peptide bond between Ala104 and Pro105 that switches between cis and trans in the two global structures are labeled. In (d), cis ASIP-YY and AgRP(87-132) are superimposed.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 346, 1059-1070) copyright 2005.

Figures were selected by the author.