6log | pdb_00006log
Crystal structure of human CCL5-12AAA14 mutant
Structural highlights
FunctionCCL5_HUMAN Chemoattractant for blood monocytes, memory T-helper cells and eosinophils. Causes the release of histamine from basophils and activates eosinophils. Binds to CCR1, CCR3, CCR4 and CCR5. One of the major HIV-suppressive factors produced by CD8+ T-cells. Recombinant RANTES protein induces a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV). The processed form RANTES(3-68) acts as a natural chemotaxis inhibitor and is a more potent inhibitor of HIV-1-infection. The second processed form RANTES(4-68) exhibits reduced chemotactic and HIV-suppressive activity compared with RANTES(1-68) and RANTES(3-68) and is generated by an unidentified enzyme associated with monocytes and neutrophils.[1] [2] [3] [4] [5] Publication Abstract from PubMedCC-type chemokine ligand 5 (CCL5) has been known to regulate immune responses by mediating the chemotaxis of leukocytes. Depending on the environment, CCL5 forms different orders of oligomers to interact with targets and create functional diversity. A recent CCL5 trimer structure revealed that the N-terminal conversed F12-A13-Y14 ((12)FAY(14)) sequence is involved in CCL5 aggregation. The CCL5-(12)AAA(14) mutant with two mutations had a deficiency in the formation of high-order oligomers. In the study, we clarify the respective roles of F12 and Y14 through NMR analysis and structural determination of the CCL5-(12)AAA(14) mutant where F12 is involved in the dimer assembly and Y14 is involved in aggregation. The CCL5-(12)AAA(14) structure contains a unique dimer packing. The backbone pairing shifts for one-residue in the N-terminal interface, when compared to the native CCL5 dimer. This difference creates a new structural orientation and leads to the conclusion that F12 confines the native CCL5 dimer configuration. Without F12 anchoring in the position, the interfacial backbone pairing is permitted to slide. Structural plasticity occurs in the N-terminal interaction. This is the first case to report this structural rearrangement through mutagenesis. The study provides a new idea for chemokine engineering and complements the understanding of CCL5 oligomerization and the role of the (12)FAY(14) sequence. N-terminal Backbone Pairing Shifts in CCL5-(12)AAA(14) Dimer Interface: Structural Significance of the FAY Sequence.,Li JY, Chen YC, Lee YZ, Huang CH, Sue SC Int J Mol Sci. 2020 Mar 1;21(5). pii: ijms21051689. doi: 10.3390/ijms21051689. PMID:32121575[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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