The evolution of lenticular proteins: The β- and γ-crystallin super gene family

Lubsen, Nicolette H.; Aarts, H.J.M.; Schoenmakers, John G.G.

doi:10.1016/0079-6107(88)90010-7

Cited by 174 publications

(73 citation statements)

References 72 publications

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“…All known c-crystallins from extant vertebrate species have duplicated Greek key domains that are presumably evolved by gene duplication and gene fusion from an ancestral single domain crystallin. 6,7 In fact, such single domain crystallins have been identified in the Sea squirt Ciona, 8 descendants of lineages that are candidates for the origin of the vertebrates.…”

Section: Introductionmentioning

confidence: 99%

β‐strand interactions at the domain interface critical for the stability of human lens γD‐crystallin

2009

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Human age-onset cataracts are believed to be caused by the aggregation of partially unfolded or covalently damaged lens crystallin proteins; however, the exact molecular mechanism remains largely unknown. We have used microseconds of molecular dynamics simulations with explicit solvent to investigate the unfolding process of human lens cD-crystallin protein and its isolated domains. A partially unfolded folding intermediate of cD-crystallin is detected in simulations with its C-terminal domain (C-td) folded and N-terminal domain (N-td) unstructured, in excellent agreement with biochemical experiments. Our simulations strongly indicate that the stability and the folding mechanism of the N-td are regulated by the interdomain interactions, consistent with experimental observations. A hydrophobic folding core was identified within the C-td that is comprised of a and b strands from the Greek key motif 4, the one near the domain interface. Detailed analyses reveal a surprising non-native surface salt-bridge between Glu135 and Arg142 located at the end of the ab folded hairpin turn playing a critical role in stabilizing the folding core. On the other hand, an in silico single E135A substitution that disrupts this non-native Glu135-Arg142 salt-bridge causes significant destabilization to the folding core of the isolated C-td, which, in turn, induces unfolding of the N-td interface. These findings indicate that certain highly conserved charged residues, that is, Glu135 and Arg142, of cD-crystallin are crucial for stabilizing its hydrophobic domain interface in native conformation, and disruption of charges on the cD-crystallin surface might lead to unfolding and subsequent aggregation.

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Section: Introductionmentioning

confidence: 99%

β‐strand interactions at the domain interface critical for the stability of human lens γD‐crystallin

2009

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“…All known βγ-crystallins from extant vertebrate species have duplicated Greek key domains that are presumably evolved by gene duplication and gene fusion from an ancestral single domain crystallin (24,25), as suggested by the high sequence and structural similarity of the two domains. In fact, such single domain crystallins have been identified-for example, in the Sea squirt Ciona (26).…”

Section: Simulations Of Oligomerization Of Aggregation-prone Monomericmentioning

confidence: 99%

Aggregation of γ-crystallins associated with human cataracts via domain swapping at the C-terminal β-strands

Das

King

Zhou

2011

Proc. Natl. Acad. Sci. U.S.A.

124

148

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The prevalent eye disease age-onset cataract is associated with aggregation of human γD-crystallins, one of the longest-lived proteins. Identification of the γ-crystallin precursors to aggregates is crucial for developing strategies to prevent and reverse cataract. Our microseconds of atomistic molecular dynamics simulations uncover the molecular structure of the experimentally detected aggregation-prone folding intermediate species of monomeric native γD-crystallin with a largely folded C-terminal domain and a mostly unfolded N-terminal domain. About 30 residues including a, b, and c strands from the Greek Key motif 4 of the C-terminal domain experience strong solvent exposure of hydrophobic residues as well as partial unstructuring upon N-terminal domain unfolding. Those strands comprise the domain-domain interface crucial for unusually high stability of γD-crystallin. We further simulate the intermolecular linkage of these monomeric aggregation precursors, which reveals domain-swapped dimeric structures. In the simulated dimeric structures, the N-terminal domain of one monomer is frequently found in contact with residues 135-164 encompassing the a, b, and c strands of the Greek Key motif 4 of the second molecule. The present results suggest that γD-crystallin may polymerize through successive domain swapping of those three C-terminal β-strands leading to age-onset cataract, as an evolutionary cost of its very high stability. Alanine substitutions of the hydrophobic residues in those aggregation-prone β-strands, such as L145 and M147, hinder domain swapping as a pathway toward dimerization. These findings thus provide critical molecular insights onto the initial stages of age-onset cataract, which is important for understanding protein aggregation diseases.

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“…These crystallographic findings are consistent with hydrodynamic (10,16,17) and equilibrium (18,19) measurements performed on these proteins in dilute aqueous solutions. Furthermore, both the N-and C-terminal peptide segments of the -crystallins are projected outside the protein globular domains like extended arms (4,10). B1-Crystallin, which comprises 9% of the total crystallins in a newborn human lens (5,9,20), undergoes extensive in vivo truncation of the N-terminal arm.…”

mentioning

confidence: 99%

“…Crystallins, which are the major structural proteins in the eye lens, are responsible for maintaining the spatial homogeneity of the refractive index. In the mammalian lenses, crystallins can be divided into three major classes: the R-crystallins, which form large oligomers (≈800 kDa); the -crystallins, which form oligomers ranging from 50 to 200 kDa; and the γ-crystallins, which remain monomers (21 kDa) (3,4).…”

mentioning

confidence: 99%

Oligomerization and Phase Transitions in Aqueous Solutions of Native and Truncated Human βB1-Crystallin

Annunziata

Pande

et al. 2005

Biochemistry

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Human B1-crystallin is a major eye-lens protein that undergoes in vivo truncation at the N-terminus with aging. By studying native B1 and truncated B1∆N41, which mimics an age-related in vivo truncation, we have determined quantitatively the effect of truncation on the oligomerization and phase transition properties of B1 aqueous solutions. The oligomerization studies show that the energy of attraction between the B1∆N41 proteins is about 10% greater than that of the B1 proteins. We have found that B1∆N41 aqueous solutions undergo two distinct types of phase transitions. The first phase transition involves an initial formation of thin rodlike assemblies, which then evolve to form crystals. The induction time for the formation of rodlike assemblies is sensitive to oligomerization. The second phase transition can be described as liquid-liquid phase separation (LLPS) accompanied by gelation within the protein-rich phase. We refer to this process as heterogeneous gelation. These two phase transitions are not observed in the case of B1 aqueous solutions. However, upon the addition of poly(ethylene glycol) (PEG), we observe heterogeneous gelation also for B1. Our PEG experiments allow us to estimate the difference in phase separation temperatures between B1 and B1∆N41. This difference is consistent with the increase in energy of attraction found in our oligomerization studies. Our work suggests that truncation is a cataractogenic modification since it favors protein condensation and the consequent formation of light scattering elements, and highlights the importance of the N-terminus of B1 in maintaining lens transparency.

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The evolution of lenticular proteins: The β- and γ-crystallin super gene family

Cited by 174 publications

References 72 publications

β‐strand interactions at the domain interface critical for the stability of human lens γD‐crystallin

β‐strand interactions at the domain interface critical for the stability of human lens γD‐crystallin

Aggregation of γ-crystallins associated with human cataracts via domain swapping at the C-terminal β-strands

Oligomerization and Phase Transitions in Aqueous Solutions of Native and Truncated Human βB1-Crystallin

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