Abstract
G protein-coupled receptor kinases (GRKs) are members of the protein kinase A, G, and C families (AGC) and play a central role in mediating G protein-coupled receptor phosphorylation and desensitization. One member of the family, GRK5, has been implicated in several human pathologies, including heart failure, hypertension, cancer, diabetes, and Alzheimer disease. To gain mechanistic insight into GRK5 function, we determined a crystal structure of full-length human GRK5 at 1.8 Å resolution. GRK5 in complex with the ATP analog 5'-adenylyl β,γ-imidodiphosphate or the nucleoside sangivamycin crystallized as a monomer. The C-terminal tail (C-tail) of AGC kinase domains is a highly conserved feature that is divided into three segments as follows: the C-lobe tether, the active-site tether (AST), and the N-lobe tether (NLT). This domain is fully resolved in GRK5 and reveals novel interactions with the nucleotide and N-lobe. Similar to other AGC kinases, the GRK5 AST is an integral part of the nucleotide-binding pocket, a feature not observed in other GRKs. The AST also mediates contact between the kinase N- and C-lobes facilitating closure of the kinase domain. The GRK5 NLT is largely displaced from its previously observed position in other GRKs. Moreover, although the autophosphorylation sites in the NLT are >20 Å away from the catalytic cleft, they are capable of rapid cis-autophosphorylation suggesting high mobility of this region. In summary, we provide a snapshot of GRK5 in a partially closed state, where structural elements of the kinase domain C-tail are aligned to form novel interactions to the nucleotide and N-lobe not previously observed in other GRKs.
Highlights
GRK5 is implicated in several human pathologies, but relatively little is known about its structure and function
We provide a snapshot of GRK5 in a partially closed state, where structural elements of the kinase domain C-terminal tail (C-tail) are aligned to form novel interactions to the nucleotide and N-lobe not previously observed in other G protein-coupled receptor kinases (GRKs)
Crystal Structure of GRK5—Previous studies suggest that the crystallization of ligand-free GRKs is very difficult because only an ϳ8 Å crystal structure of apo-GRK1 has been reported [24]
Summary
GRK5 is implicated in several human pathologies, but relatively little is known about its structure and function. Atomic Structure of GRK5 growth [15] and metastasis [16], Parkinson disease with dementia [17], synuclein phosphorylation and aggregation in sporadic Parkinson disease [18], and Alzheimer pathology in mice and humans [19], possibly due to its role in neurite outgrowth, learning, and memory [20] Taken together, these studies reveal that GRK5 is implicated in many different human diseases and may provide an important therapeutic target in the treatment of cardiovascular disease, neurological and metabolic disorders, and cancer. In contrast to crystal structures of GRK1 and GRK6, GRK5 is a monomer in the crystal and contains a well ordered kinase domain C-tail that includes interactions between the active-site tether and bound nucleotide Such studies have high significance for understanding GRKs and how structure/function changes might mediate pathological consequences. These studies should set the stage for developing strategies to regulate GRK5 function in the treatment of disease
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