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Crystal structure of human protein-tyrosine phosphatase SHP-1
Jian Yang1, Lijun Liu, Dandan He
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Abstract:
SHP-1 is a cytosolic protein-tyrosine phosphatase that behaves as a negative regulator in eukaryotic cellular signaling pathways. To understand its regulatory mechanism, we have determined the crystal structure of the C-terminal truncated human SHP-1 in the inactive conformation at 2.8-A resolution and refined the structure to a crystallographic R-factor of 24.0%. The three-dimensional structure shows that the ligand-free SHP-1 has an auto-inhibited conformation. Its N-SH2 domain blocks the catalytic domain and keeps the enzyme in the inactive conformation, which supports that the phosphatase activity of SHP-1 is primarily regulated by the N-SH2 domain. In addition, the C-SH2 domain of SHP-1 has a different orientation from and is more flexible than that of SHP-2, which enables us to propose an enzymatic activation mechanism in which the C-SH2 domains of SHPs could be involved in searching for phosphotyrosine activators.
Insights
The study reveals how SHP-1 (SH2-containing phosphatase-1) is auto-inhibited in its inactive state. The N-SH2 domain blocks the catalytic site, suggesting it
Area of Science:
- Biochemistry
- Structural Biology
- Cellular Signaling
Background:
- SHP-1 is a crucial negative regulator in eukaryotic cellular signaling pathways.
- Understanding SHP-1's regulatory mechanism is key to deciphering cellular communication.
Purpose of the Study:
- To determine the crystal structure of C-terminal truncated human SHP-1.
- To elucidate the auto-inhibited conformation and regulatory mechanism of SHP-1.
Main Methods:
- X-ray crystallography was used to determine the structure of human SHP-1.
- Structure refinement was performed to a crystallographic R-factor of 24.0% at 2.8-A resolution.
Main Results:
- The crystal structure of ligand-free SHP-1 revealed an auto-inhibited conformation.
- The N-SH2 domain was observed to block the catalytic domain, maintaining enzyme inactivity.
- The C-SH2 domain exhibited distinct orientation and flexibility compared to SHP-2.
Conclusions:
- SHP-1's phosphatase activity is primarily regulated by its N-SH2 domain.
- A proposed activation mechanism involves the C-SH2 domain interacting with phosphotyrosine activators.