Structural and functional analysis of the constitutively active C-C chemokine receptor type 1 (CCR1)...

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منو

" Structural and functional analysis of the constitutively active C-C chemokine receptor type 1 (CCR1) / "
Gilliland, Christian Taylor

Document Type	:	Latin Dissertation
Language of Document	:	English
Record Number	:	897403
Doc. No	:	TL4w19x7kx
Main Entry	:	Mueller, Lisa
Title & Author	:	Structural and functional analysis of the constitutively active C-C chemokine receptor type 1 (CCR1) /\ Gilliland, Christian Taylor
Date	:	2013
student score	:	2013
Abstract	:	Chemokine receptors belong to the G protein-coupled receptor (GPCR) family of proteins and are critical mediators of the directed migration of leukocytes in innate and adaptive immune responses. Understanding the behavior of chemokine receptors under basal and agonist- stimulated conditions is essential to developing effective therapeutics for inflammatory and autoimmune diseases. For the first time, the constitutive activity of the C-C chemokine receptor type 1 (CCR1) is uncovered through ligand-independent cellular migration, constitutive phosphorylation and association with [beta]-arrestin-2, and continual internalization followed by recycling back to the plasma membrane. Initial data suggests that CCR1 can act as a scavenging receptor to sequester chemokines intracellularly without canonical G protein signaling, thereby providing biological relevance to receptor constitutive activity. A Ser/Thr-rich cluster in the distal carboxy-terminal tail of CCR1 is identified as the major site of basal phosphorylation and fulfills a necessary, but not sufficient, role in pre-coupling to [beta]-arrestin-2. Site-directed mutagenesis of receptor transmembrane domains and conserved DRY motif has identified residues important for stabilizing CCR1 in a constitutively active state. Activation of CCR1 primarily leads to a conformational rearrangement with [beta]- arrestin-2, while endogenous chemokines induce this change with differential potency and efficacy. Lastly, small metal ion chelator molecules are able to activate desensitization and down-modulation of CCR1 with similar efficacy to natural ligands. Taken together, the work presented herein underlies the complexity of CCR1 function in the presence and absence of ligand and provides new avenues for therapeutic targeting
Added Entry	:	Gilliland, Christian Taylor
Added Entry	:	UC San Diego