Crystal structure of human protein-tyrosine phosphatase SHP-1

UMMS Affiliation

Program in Molecular Medicine

Publication Date


Document Type



Amino Acid Sequence; Crystallography, X-Ray; Humans; Intracellular Signaling Peptides and Proteins; Models, Molecular; Molecular Sequence Data; Protein Conformation; Protein Structure, Secondary; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases; Sensitivity and Specificity; Sequence Alignment; Sequence Homology, Amino Acid


Life Sciences | Medicine and Health Sciences


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.

DOI of Published Version



J Biol Chem. 2003 Feb 21;278(8):6516-20. Epub 2002 Dec 13. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of biological chemistry

Related Resources

Link to Article in PubMed

PubMed ID