Phospholipid Binding: GRAM Domain

The GRAM domain of MTMR2.

Domain Binding and Function

The GRAM (Glucosyltransferases, Rab-like GTPase activators and Myotubularins) domain is approximately 70 amino acids in length and consists of a 7-stranded β sandwich and a C-terminal α-helix. GRAM domains are commonly found in myotubularin family phosphatases and are thought to occur in ~180 proteins. The GRAM domain of the myotubularin related protein 2 (MTMR2) shows an unexpectedly large fold similar to that found in the pleckstrin homology (PH) domain. Proteins containing GRAM domains are predominately involved in membrane-coupled processes. Functional studies demonstrate that the GRAM domain is involved in PI-(3,5)P2 substrate recognition, PI-(3)-P/PI-(5)-P dependent oligomerization and PI-(5)-P specific allosteric activation of myotubularin phosphatases. Corresponding gene mutations affecting GRAM domain structure can lead to human disorders including X-linked congenital myopathy.

Structure

The MTMR2 GRAM sequence forms five β strands that are part of a larger motif that structurally adopts a PH domain fold. The GRAM domain along with immediately adjacent amino acid residues form a tertiary structure that consists of a 7-stranded β sandwich with a C-terminal α-helix. The structure of the MTMR2 GRAM domain is very similar to the pleckstrin PH domain; given highly conserved residues among GRAM core domains, other GRAM domains would likely share similar PH domain folds.

Structure Reference

  1. Begley, M.J., et al. (2003) Mol. Cell 12(6), 1391–1402.

Examples of Domain Proteins

Phospholipid Binding: GRAM Domain

Binding Examples

Gram domain protein Specific Phosphoinositide ligands
MTMR2 PI-(3,5)-P2, PI-(5)-P
MTM1, MTMR3, and MTMR6 PI-(5)-P