Abstract
ABSTRACTKaposi’s sarcoma-associated herpesvirus (KSHV) encodes a viral G protein-coupled receptor, KSHV-GPCR, that contributes to KSHV immune evasion and pathogenesis of Kaposi’s Sarcoma. KSHV-GPCR shares a high similarity with CXC chemokine receptors CXCR2 and can be activated by selected chemokine ligands. KSHV-GPCR is also unique for its constitutive activity by coupling to various G proteins. We investigated the structural basis of ligand-dependent as well as constitutive activity of KSHV-GPCR through cryo-EM structural determination of KSHV-GPCR-Gi signaling complexes with and without bound CXCL1 chemokine ligand. Analysis of the apo-KSHV-GPCR-Gi structure, with an overall resolution of 2.81 Å, unraveled the involvement of extracellular loop 2 in constitutive activation of the receptor. This and other structural motifs serve to stabilize the constitutively-active KSHV-GPCR. The CXCL1-bound KSHV-GPCR-Gi structure was solved to an overall resolution of 3.01 Å, and showed a two-site binding of the chemokine by the receptor. Together with functional validations, this work shed light on the structural basis for constitutive as well as CXCL1-induced activation of KSHV-GPCR. The work also demonstrates evolutionary advantage in immune evasion by KSHV through its virally encoded chemokine receptor, with potential implications in developing therapeutic strategies for KSHV infection.
Publisher
Cold Spring Harbor Laboratory
Reference33 articles.
1. Modulation of the immune system by Kaposi's sarcoma-associated herpesvirus
2. Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation
3. G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator
4. Activation of the β2-Adrenergic Receptor Involves Disruption of an Ionic Lock between the Cytoplasmic Ends of Transmembrane Segments 3 and 6
5. Burg, J.S. , Ingram, J.R. , Venkatakrishnan, A.J. , Jude, K.M. , Dukkipati, A. , Feinberg, E.N. , Angelini, A. , Waghray, D. , Dror, R.O. , Ploegh, H.L. , and Garcia, K.C. (2015).