Structural basis for CD44 recognition by ERM proteins

Area of Science:

• Molecular Biology
• Structural Biology
• Cell Biology

Background:

• CD44 is a key adhesion molecule and hyaluronan receptor involved in cell adhesion and migration.
• Full CD44 activity requires binding to ERM proteins, but its cytoplasmic region lacks a known ERM binding motif.
• Understanding CD44-ERM interactions is crucial for various physiological and pathological processes.

Purpose of the Study:

• To elucidate the structural basis of CD44 cytoplasmic region binding to ERM proteins.
• To investigate the mechanism of CD44-ERM interaction in the absence of a canonical Motif-1 sequence.
• To provide insights into CD44's role in cell adhesion, migration, and potential nuclear translocation.

Main Methods:

• Ultracentrifugation sedimentation studies
• Circular dichroism measurements
• Crystal structure determination of the radixin FERM domain complexed with a CD44 cytoplasmic peptide

Main Results:

• The CD44 cytoplasmic peptide adopts an extended monomeric form.
• A specific sequence (KKKLVIN) in CD44 forms a beta strand that binds subdomain C of the radixin FERM domain.
• The binding mode is distinct from Motif-1 interactions seen in other adhesion molecules, resembling NEP binding.
• Hydrophobic interactions and hydrogen bonds stabilize the CD44-FERM domain complex.

Conclusions:

• CD44 utilizes a unique mechanism for ERM protein binding, demonstrating FERM domain versatility.
• This binding may facilitate CD44 tail release for nuclear translocation via regulated intramembrane proteolysis.
• The findings provide a structural foundation for understanding Smad1 interactions with activated CD44-ERM complexes.