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J Biol Chem, Vol. 274, Issue 52, 37301-37306, December 24, 1999
Motif
Domain*
From the UCLA-DOE Laboratory of Structural Biology and Molecular
Medicine and Department of Chemistry and Biochemistry, UCLA,
Los Angeles, California 90095
The sterile 
motif (SAM) domain is a protein
module found in many diverse signaling proteins. SAM domains in some
systems have been shown to self-associate. Previous crystal structures of an EphA4-SAM domain dimer (Stapleton, D., Balan, I., Pawson, T., and
Sicheri, F. (1999) Nat. Struct. Biol. 6, 44-49) and a possible EphB2-SAM oligomer (Thanos, C. D., Goodwill, K. E.,
and Bowie, J. U. (1999) Science 283, 833-836) both
revealed large interfaces comprising an exchange of N-terminal peptide
arms. Within the arm, a conserved hydrophobic residue (Tyr-8 in the EphB2-SAM structure or Phe-910 in the EphA4-SAM structure) is anchored
into a hydrophobic cleft on a neighboring molecule. Here we have solved
a new crystal form of the human EphB2-SAM domain that has the same
overall SAM domain fold yet has no substantial intermolecular contacts.
In the new structure, the N-terminal peptide arm of the EphB2-SAM
domain protrudes out from the core of the molecule, leaving both the
arm (including Tyr-8) and the hydrophobic cleft solvent-exposed. To
verify that Tyr-8 is solvent-exposed in solution, we made a Tyr-8 to
Ala-8 mutation and found that the EphB2-SAM domain structure and
stability were only slightly altered. These results suggest that Tyr-8
is not part of the hydrophobic core of the EphB2-SAM domain and is
conserved for functional reasons. Cystallographic evidence suggests a
possible role for the N-terminal arm in oligomerization. In the absence
of a direct demonstration of biological relevance, however, the
functional role of the N-terminal arm remains an open question.
To whom correspondence should be addressed. Tel.: 310-206-4747;
Fax: 310-206-4749; E-mail: bowie@mbi.ucla.edu.
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