7ken
Protein Tyrosine Phosphatase 1B, D289A mutant, apo stateProtein Tyrosine Phosphatase 1B, D289A mutant, apo state
Structural highlights
FunctionPTN1_HUMAN Tyrosine-protein phosphatase which acts as a regulator of endoplasmic reticulum unfolded protein response. Mediates dephosphorylation of EIF2AK3/PERK; inactivating the protein kinase activity of EIF2AK3/PERK. May play an important role in CKII- and p60c-src-induced signal transduction cascades. May regulate the EFNA5-EPHA3 signaling pathway which modulates cell reorganization and cell-cell repulsion.[1] [2] Publication Abstract from PubMedAllosteric regulation enables dynamic adjustments to protein function that permit tight control over cellular biochemistry. Discrepancies in the allosteric systems of related proteins can thus reveal important differences in their susceptibilities to influential stimuli (e.g., allosteric ligands, mutations, or post-translational modifications). This study uses an optogenetic actuator as a tool to compare the allosteric systems of two structurally related regulatory proteins: protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TCPTP). It begins with an interesting observation: The fusion of a protein light switch to the allosterically influential alpha7 helix of PTP1B permits optical modulation of its catalytic activity, but a similar fusion to TCPTP does not. A subsequent analysis of different PTP chimeras shows that replacing regions of TCPTP with homologous regions from PTP1B can enhance photocontrol; as TCPTP becomes more "PTP1B-like", its photosensitivity increases. Interestingly, the structural changes required for photocontrol also enhance the sensitivity of TCPTP to other allosteric inputs, notably, an allosteric inhibitor and a newly reported activating mutation. Our findings indicate that the allosteric functionality of the alpha7 helix of PTP1B is not conserved across the PTP family and highlight residues necessary to transfer this functionality to other PTPs. More broadly, our results suggest that simple gene fusion events can strengthen allosteric communication within individual protein domains and describe an intriguing application for optogenetic actuators as structural probes-a sort of physically disruptive "ratchet"-for studying protein allostery. Optogenetic Analysis of Allosteric Control in Protein Tyrosine Phosphatases.,Hongdusit A, Fox JM Biochemistry. 2021 Feb 2;60(4):254-258. doi: 10.1021/acs.biochem.0c00841. Epub, 2021 Jan 15. PMID:33450156[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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