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Decrease in Protein Solubility and Cataract Formation Caused by the Pro23 to Thr Mutation in Human D-Crystallin,
 

Summary: Decrease in Protein Solubility and Cataract Formation Caused by the Pro23 to Thr
Mutation in Human D-Crystallin,
Ajay Pande, Onofrio Annunziata,,| Neer Asherie,, Olutayo Ogun,# George B. Benedek,,# and Jayanti Pande*,#
Department of Physics and Center for Materials Science and Engineering, and Materials Processing Center,
Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
ReceiVed September 21, 2004; ReVised Manuscript ReceiVed NoVember 23, 2004
ABSTRACT: The P23T mutation in the human D-crystallin gene has in recent years been associated with
a number of well known cataract phenotypes. To understand the molecular mechanism of lens opacity
caused by this mutation, we expressed human D-crystallin (HGD), the P23T mutant, and other related
mutant proteins in Escherichia coli and compared the structures and thermodynamic properties of these
proteins in Vitro. The results show that the cataract-causing mutation P23T does not exhibit any significant
structural change relative to the native protein. However, in marked contrast to the native protein, the
mutant shows a dramatically lowered solubility. The reduced solubility results from the association of the
P23T mutant to form a new condensed phase that contains clusters of the mutant protein. The monomer-
cluster equilibrium is represented by a solubility curve in the phase diagram. When the solubility limit is
exceeded, the mutant protein forms the condensed phase after a nucleation time of 10-20 min. We found
that the solubility of the P23T mutant exhibits an inverse dependence on temperature, i.e., the protein
clusters are increasingly soluble as the temperature of the solution decreases. The solubility of P23T can
be substantially altered by the introduction of specific mutations at or in the immediate vicinity of residue
23. We examined the mutants P23S, P23V, P23TInsP24, and P23TN24K and found that the latter two

  

Source: Annunziata, Onofrio - Department of Chemistry, Texas Christian University
Asherie, Neer - Departments of Physics & Biology, Yeshiva University
Benedek, George B. - Department of Physics, Massachusetts Institute of Technology (MIT)

 

Collections: Biology and Medicine; Chemistry; Physics