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Blood, 15 September 2001, Vol. 98, No. 6, pp. 1645-1653
PLENARY PAPER
Dynamic molecular modeling of pathogenic mutations in the
spectrin self-association domain
Zhushan Zhang,
Scott A. Weed,
Patrick G. Gallagher, and
Jon S. Morrow
From the Departments of Pathology, Pediatrics, and
Molecular, Cellular, and Developmental Biology, Yale University, New
Haven, CT.
Disruption of spectrin self-association underlies many inherited
hemolytic disorders. Using dynamic modeling and energy minimization, the 3-dimensional structure of the self-association domain has been
estimated in human erythrocyte spectrin and the structural consequences
of 17 elliptogenic mutations determined. The predicted structure of the
normal self-association domain was remarkably similar to the crystal
structure of the Drosophila  -spectrin 14th repeat unit,
despite replacement in the human sequence of over 70% of the amino
acids relative to fly spectrin, including 2 prolines in the human
sequence that appear in helical regions of the fly structure. The
predicted structure placed all hydrophilic residues at the surface and
identified 4 salt bridges, 9 hydrophobic interactions, and 4 H-bonds
that stabilize the native self-association unit. Remarkably, every
pathologic point mutation, including seemingly conservative
substitutions such as G for A, A for V, or K for R (single-letter amino
acid codes), led to conformational rearrangements in the predicted
structure. The degree of structural disruption, as measured by
root-mean-square deviation of the predicted backbone structure from the
Drosophila structure, correlated strongly with the severity
of clinical disease associated with each mutation. This approach thus
enables an accurate prediction, from the primary sequence, of the
clinical consequences of specific point mutations in spectrin. The
3-dimensional structure of the self-association domain derived
here is likely to be accurate. It provides a powerful heuristic model
for understanding how point mutations disrupt cytoskeletal function in
a variety of hemolytic disorders.
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