Contact rearrangements form coupled networks from local motions in allosteric proteins

被引:82
作者
Daily, Michael D. [3 ]
Upadhyaya, Tarak J. [2 ]
Gray, Jeffrey J. [1 ,3 ]
机构
[1] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA
[2] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA
[3] Johns Hopkins Univ, Program Mol & Computat Biophys, Baltimore, MD 21218 USA
关键词
allosteric mechanism; small-world network; graph theory; conformational change; signal propagation;
D O I
10.1002/prot.21800
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Allosteric proteins bind an effector molecule at one site resulting in a functional change at a second site. We hypothesize that networks of contacts altered, formed, or broken are a significant contributor to allosteric communication in proteins. In this work, we identify which interactions change significantly between the residue-residue contact networks of two allosteric structures and then organize these changes into graphs. We perform the analysis on 15 pairs of allosteric structures with effector and substrate each present in at least one of the two structures. Most proteins exhibit large, dense regions of contact rearrangement, and the graphs form connected paths between allosteric effector and substrate sites in five of these proteins. In the remaining 10 proteins, large-scale conformational changes such as rigid-body motions are likely required in addition to contact rearrangement networks to account for substrate-effector communication. On average, clusters which contain at least one substrate or effector molecule comprise 20% of the protein. These allosteric graphs are small worlds; that is, they typically have mean shortest path lengths comparable to those of corresponding random graphs and average clustering coefficients enhanced relative to those of random graphs. The networks capture 60-80% of known allostery-perturbing mutants in three proteins, and the metrics degree and closeness are statistically good discriminators of mutant residues from nonmutant residues within the networks in two of these three proteins. For two proteins, coevolving clusters of residues which have been hypothesized to be allosterically important differ from the regions with the most contact rearrangement. Residues and contacts which modulate normal mode fluctuations also often participate in the contact rearrangement networks. In summary, residue-residue contact rearrangement networks provide useful representations of the portions of allosteric pathways resulting from coupled local motions.
引用
收藏
页码:455 / 466
页数:12
相关论文
共 55 条
[1]   Error and attack tolerance of complex networks [J].
Albert, R ;
Jeong, H ;
Barabási, AL .
NATURE, 2000, 406 (6794) :378-382
[2]   Classes of small-world networks [J].
Amaral, LAN ;
Scala, A ;
Barthélémy, M ;
Stanley, HE .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (21) :11149-11152
[3]   Network analysis of protein structures identifies functional residues [J].
Amitai, G ;
Shemesh, A ;
Sitbon, E ;
Shklar, M ;
Netanely, D ;
Venger, I ;
Pietrokovski, S .
JOURNAL OF MOLECULAR BIOLOGY, 2004, 344 (04) :1135-1146
[4]   Anatomy of a structural pathway for activation of the catalytic domain of Src kinase Hck [J].
Banavali, Nilesh K. ;
Roux, Benoit .
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2007, 67 (04) :1096-1112
[5]   Emergence of scaling in random networks [J].
Barabási, AL ;
Albert, R .
SCIENCE, 1999, 286 (5439) :509-512
[6]   STRUCTURAL MECHANISM FOR GLYCOGEN-PHOSPHORYLASE CONTROL BY PHOSPHORYLATION AND AMP [J].
BARFORD, D ;
HU, SH ;
JOHNSON, LN .
JOURNAL OF MOLECULAR BIOLOGY, 1991, 218 (01) :233-260
[7]   A test of the role of the proximal histidines in the Perutz model for cooperativity in haemoglobin [J].
Barrick, D ;
Ho, NT ;
Simplaceanu, V ;
Dahlquist, FW ;
Ho, C .
NATURE STRUCTURAL BIOLOGY, 1997, 4 (01) :78-83
[8]   AN IMPROVED INDEX OF CENTRALITY [J].
BEAUCHAMP, MA .
BEHAVIORAL SCIENCE, 1965, 10 (02) :161-163
[9]  
Berg J.M., 2002, Biochemistry, P465
[10]   The Protein Data Bank [J].
Berman, HM ;
Westbrook, J ;
Feng, Z ;
Gilliland, G ;
Bhat, TN ;
Weissig, H ;
Shindyalov, IN ;
Bourne, PE .
NUCLEIC ACIDS RESEARCH, 2000, 28 (01) :235-242