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SRY and human sex determination: The basic tail of the HMG box functions as a kinetic clamp to augment DNA bending
Phillips N.B.3; Jancso-Radek A.3; Ittah V.2; Singh R.3; Chan G.3; Haas E.2; Weiss M.A.3
2006-04-21
Source PublicationJournal of Molecular Biology
ISSN00222836
Volume358Issue:1Pages:172-192
Abstract

Human testis-determining factor SRY contains a high-mobility-group (HMG) box, an α-helical DNA-binding domain that binds within an expanded minor groove to induce DNA bending. This motif is flanked on the C-terminal end by a basic tail, which functions both as a nuclear localization signal and accessory DNA-binding element. Whereas the HMG box is broadly conserved among otherwise unrelated transcription factors, tails differ in sequence and mode of DNA binding. Contrasting examples are provided by SRY and lymphoid enhancer factor 1 (LEF-1): whereas the SRY tail remains in the minor groove distal to the HMG box, the LEF-1 tail binds back across the center of the bent DNA site. The LEF-1 tail relieves electrostatic repulsion that would otherwise be incurred within the compressed major groove to enable sharp DNA bending with high affinity. Here, we demonstrate that the analogous SRY tail functions as a "kinetic clamp" to regulate the lifetime of the bent DNA complex. As in LEF-1, partial truncation of the distal SRY tail reduces specific DNA affinity and DNA bending, but these perturbations are modest: binding is reduced by only 1.8-fold, and bending by only 7-10°. "Tailed" and truncated SRY complexes exhibit similar structures (as probed by NMR) and distributions of long-range conformational substates (as probed by time-resolved fluorescence resonance energy transfer). Surprisingly, however, the SRY tail retards dissociation of the protein-DNA complex by 20-fold. The marked and compensating changes in rates of association and dissociation observed on tail truncation, disproportionate to perturbations in affinity or structure, suggest that this accessory element functions as a kinetic clamp to regulate the lifetime of the SRY-DNA complex. We speculate that the kinetic stability of a bent DNA complex is critical to the assembly and maintenance of a sex-specific transcriptional pre-initiation complex. © 2006 Elsevier Ltd. All rights reserved.

KeywordGene Regulation Protein Structure Intersex Abnormalities Gonadal Dysgenesis Human Development
DOI10.1016/j.jmb.2006.01.060
URLView the original
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemistry & Molecular Biology
WOS IDWOS:000236870700015
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Cited Times [WOS]:27   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorWeiss M.A.
Affiliation1.Epicentre
2.Bar-Ilan University
3.CASE School of Medicine
Recommended Citation
GB/T 7714
Phillips N.B.,Jancso-Radek A.,Ittah V.,et al. SRY and human sex determination: The basic tail of the HMG box functions as a kinetic clamp to augment DNA bending[J]. Journal of Molecular Biology,2006,358(1):172-192.
APA Phillips N.B..,Jancso-Radek A..,Ittah V..,Singh R..,Chan G..,...&Weiss M.A..(2006).SRY and human sex determination: The basic tail of the HMG box functions as a kinetic clamp to augment DNA bending.Journal of Molecular Biology,358(1),172-192.
MLA Phillips N.B.,et al."SRY and human sex determination: The basic tail of the HMG box functions as a kinetic clamp to augment DNA bending".Journal of Molecular Biology 358.1(2006):172-192.
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