Myotubularin-related proteins are a large subfamily of protein tyrosine 
phosphatases (PTPs) that dephosphorylate D3-phosphorylated inositol lipids. 
Mutations in members of the myotubularin family cause the human neuromuscular 
disorders myotubular myopathy and type 4B Charcot-Marie-Tooth syndrome. The 
crystal structure of a representative member of this family, MTMR2, reveals a 
phosphatase domain that is structurally unique among PTPs. A series of mutants 
are described that exhibit altered enzymatic activity and provide insight into 
the specificity of myotubularin phosphatases toward phosphoinositide substrates. 
The structure also reveals that the GRAM domain, found in myotubularin family 
phosphatases and predicted to occur in approximately 180 proteins, is part of a 
larger motif with a pleckstrin homology (PH) domain fold. Finally, the MTMR2 
structure will serve as a model for other members of the myotubularin family and 
provide a framework for understanding the mechanism whereby mutations in these 
proteins lead to disease.