4ra8

Structure analysis of the Mip1a P8A mutant

spinqualitylabelsall models 4ra8, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ra8 is a 5 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entry 3tn1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CCL3_HUMAN Monokine with inflammatory and chemokinetic properties. Binds to CCR1, CCR4 and CCR5. One of the major HIV-suppressive factors produced by CD8+ T-cells. Recombinant MIP-1-alpha induces a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV). Publication Abstract from PubMed CC chemokine ligands (CCLs) are 8- to 14-kDa signaling proteins involved in diverse immune functions. While CCLs share similar tertiary structures, oligomerization produces highly diverse quaternary structures that protect chemokines from proteolytic degradation and modulate their functions. CCL18 is closely related to CCL3 and CCL4 with respect to both protein sequence and genomic location, yet CCL18 has distinct biochemical and biophysical properties. Here, we report a crystal structure of human CCL18 and its oligomerization states in solution based on crystallographic and small-angle X-ray scattering analyses. Our data show that CCL18 adopts an alpha-helical conformation at its N-terminus that weakens its dimerization, explaining CCL18's preference for the monomeric state. Multiple contacts between monomers allow CCL18 to reversibly form a unique open-ended oligomer different from those of CCL3, CCL4, and CCL5. Furthermore, these differences hinge on proline 8, which is conserved in CCL3 and CCL4 but is replaced by lysine in human CCL18. Our structural analyses suggest that a mutation of proline 8 to alanine stabilizes a type 1 beta-turn at the N-terminus of CCL4 to prevent dimerization but prevents dimers from making key contacts with each other in CCL3. Thus, the P8A mutation induces depolymerization of CCL3 and CCL4 by distinct mechanisms. Finally, we used structural, biochemical, and functional analyses to unravel why insulin-degrading enzyme degrades CCL3 and CCL4 but not CCL18. Our results elucidate the molecular basis for the oligomerization of three closely related CC chemokines and suggest how oligomerization shapes CCL chemokine function. Structures of human CCL18, CCL3, and CCL4 reveal molecular determinants for quaternary structures and sensitivity to insulin-degrading enzyme.,Liang WG, Ren M, Zhao F, Tang WJ J Mol Biol. 2015 Mar 27;427(6 Pt B):1345-58. doi: 10.1016/j.jmb.2015.01.012. Epub, 2015 Jan 28. PMID:25636406 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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