Dataset Information

Nuclear Magnetic Resonance Structure of a Major Lens Protein, Human ?C-Crystallin: Role of the Dipole Moment in Protein Solubility.

ABSTRACT: A hallmark of the crystallin proteins is their exceptionally high solubility, which is vital for maintaining the high refractive index of the eye lens. Human ?C-crystallin is a major ?-crystallin whose mutant forms are associated with congenital cataracts but whose three-dimensional structure is not known. An earlier study of a homology model concluded that human ?C-crystallin has low intrinsic solubility, mainly because of the atypical magnitude and fluctuations of its dipole moment. On the contrary, the high-resolution tertiary structure of human ?C-crystallin determined here shows unequivocally that it is a highly soluble, monomeric molecule in solution. Notable differences between the orientations and interactions of several side chains are observed upon comparison to those in the model. No evidence of the pivotal role ascribed to the effect of dipole moment on protein solubility was found. The nuclear magnetic resonance structure should facilitate a comprehensive understanding of the deleterious effects of cataract-associated mutations in human ?C-crystallin.

SUBMITTER: Dixit K

PROVIDER: S-EPMC5391980 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Nuclear Magnetic Resonance Structure of a Major Lens Protein, Human γC-Crystallin: Role of the Dipole Moment in Protein Solubility.

Dixit Karuna K Pande Ajay A Pande Jayanti J Sarma Siddhartha P SP

Biochemistry 20160523 22

A hallmark of the crystallin proteins is their exceptionally high solubility, which is vital for maintaining the high refractive index of the eye lens. Human γC-crystallin is a major γ-crystallin whose mutant forms are associated with congenital cataracts but whose three-dimensional structure is not known. An earlier study of a homology model concluded that human γC-crystallin has low intrinsic solubility, mainly because of the atypical magnitude and fluctuations of its dipole moment. On the con ...[more]

PMID: 27187112

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Project description:Protein kinases are ubiquitous enzymes with critical roles in cellular processes and pathology. As a result, researchers have studied their activity and regulatory mechanisms extensively. Thousands of X-ray structures give snapshots of the architectures of protein kinases in various states of activation and ligand binding. However, the extent of and manner by which protein motions and conformational dynamics underlie the function and regulation of these important enzymes is not well understood. Nuclear magnetic resonance (NMR) methods provide complementary information about protein conformation and dynamics in solution. However, until recently, the large size of these enzymes prevented researchers from using these methods with kinases. Developments in transverse relaxation-optimized spectroscopy (TROSY)-based techniques and more efficient isotope labeling strategies are now allowing researchers to carry out NMR studies on full-length protein kinases. In this Account, we describe recent insights into the role of dynamics in protein kinase regulation and catalysis that have been gained from NMR measurements of chemical shift changes and line broadening, residual dipolar couplings, and relaxation. These findings show strong associations between protein motion and events that control kinase activity. Dynamic and conformational changes occurring at ligand binding sites and other regulatory domains of these proteins propagate to conserved kinase core regions that mediate catalytic function. NMR measurements of slow time scale (microsecond to millisecond) motions also reveal that kinases carry out global exchange processes that synchronize multiple residues and allosteric interconversion between conformational states. Activating covalent modifications or ligand binding to form the Michaelis complex can induce these global processes. Inhibitors can also exploit the exchange properties of kinases by using conformational selection to form dynamically quenched states. These investigations have revealed that kinases are highly dynamic enzymes, whose regulation by interdomain interactions, ligand binding, and covalent modifications involve changes in motion and conformational equilibrium in a manner that can be correlated with function. Thus, NMR provides a unique window into the role of protein dynamics in kinase regulation and catalysis with important implications for drug design.

Dataset Information

Nuclear Magnetic Resonance Structure of a Major Lens Protein, Human ?C-Crystallin: Role of the Dipole Moment in Protein Solubility.

Publications

Nuclear Magnetic Resonance Structure of a Major Lens Protein, Human γC-Crystallin: Role of the Dipole Moment in Protein Solubility.

Similar Datasets

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