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From Proteopedia
X-ray structure of SRPK1
Structural highlights
FunctionSRPK1_HUMAN Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing. Plays a central role in the regulatory network for splicing, controlling the intranuclear distribution of splicing factors in interphase cells and the reorganization of nuclear speckles during mitosis. Can influence additional steps of mRNA maturation, as well as other cellular activities, such as chromatin reorganization in somatic and sperm cells and cell cycle progression. Isoform 2 phosphorylates SFRS2, ZRSR2, LBR and PRM1. Isoform 2 phosphorylates SRSF1 using a directional (C-terminal to N-terminal) and a dual-track mechanism incorporating both processive phosphorylation (in which the kinase stays attached to the substrate after each round of phosphorylation) and distributive phosphorylation steps (in which the kinase and substrate dissociate after each phosphorylation event). The RS domain of SRSF1 binds first to a docking groove in the large lobe of the kinase domain of SRPK1. This induces certain structural changes in SRPK1 and/or RRM2 domain of SRSF1, allowing RRM2 to bind the kinase and initiate phosphorylation. The cycles continue for several phosphorylation steps in a processive manner (steps 1-8) until the last few phosphorylation steps (approximately steps 9-12). During that time, a mechanical stress induces the unfolding of the beta-4 motif in RRM2, which then docks at the docking groove of SRPK1. This also signals RRM2 to begin to dissociate, which facilitates SRSF1 dissociation after phosphorylation is completed. Isoform 2 can mediate hepatitis B virus (HBV) core protein phosphorylation. It plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles. Isoform 1 and isoform 2 can induce splicing of exon 10 in MAPT/TAU. The ratio of isoform 1/isoform 2 plays a decisive role in determining cell fate in K-562 leukaemic cell line: isoform 2 favors proliferation where as isoform 1 favors differentiation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedSR protein kinase 1 (SRPK1) is a constitutively active kinase, which processively phosphorylates multiple serines within its substrates, ASF/SF2. We describe crystallographic, molecular dynamics, and biochemical results that shed light on how SRPK1 preserves its constitutive active conformation. Our structure reveals that unlike other known active kinase structures, the activation loop remains in an active state without any specific intraprotein interactions. Moreover, SRPK1 remains active despite extensive mutation to the activation segment. Molecular dynamics simulations reveal that SRPK1 partially absorbs the effect of mutations by forming compensatory interactions that maintain a catalytically competent chemical environment. Furthermore, SRPK1 is similarly resistant to deletion of its spacer loop region. Based upon a model of SRPK1 bound to a segment encompassing the docking motif and active-site peptide of ASF/SF2, we suggest a mechanism for processive phosphorylation and propose that the atypical resiliency we observed is critical for SRPK1's processive activity. SR protein kinase 1 is resilient to inactivation.,Ngo JC, Gullingsrud J, Giang K, Yeh MJ, Fu XD, Adams JA, McCammon JA, Ghosh G Structure. 2007 Jan;15(1):123-33. PMID:17223538[17] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations 5 reviews cite this structure No citations found See AlsoReferences
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Categories: Homo sapiens | Large Structures | Adams JA | Aubol BE | Chakrabarti S | Fu XD | Ghosh G | Gullingsrud J | Mccammon JA | Ngo JC | Nolen B
