Characterization of Protein–Protein Interfaces

Yan, Cong; Wu, Feihong; Jernigan, Robert L.; Dobbs, Drena; Honavar, Vasant

doi:10.1007/s10930-007-9108-x

Cited by 156 publications

(132 citation statements)

References 35 publications

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“…We are inclined to suggest that the lysine side chain confers high conformational surface entropy, which is thought to interfere with protein-protein interaction. Thus, lysine residues are infrequently incorporated within the interface domains of proteins (34,64). In a corresponding manner, an analysis of the 11E7 or 6bE7 secondary structure, conformational entropy, and amino acid sequence conservation by the Surface Entropy Reduction Prediction Server identified 11E7 lysine residues 39 and 42 and 6bE7 lysine residue 49 as nonconserved, high-entropy residues which may impede the formation of protein complexes (21) (http://www.doe-mbi.ucla .edu/Services/SER).…”

Section: Discussionmentioning

confidence: 99%

Nonconserved Lysine Residues Attenuate the Biological Function of the Low-Risk Human Papillomavirus E7 Protein

Genovese

Broker

Chow

2011

J Virol

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The mucosotrophic human papillomaviruses (HPVs) are classified as high-risk (HR) or low-risk (LR) genotypes based on their neoplastic properties. We have demonstrated previously that the E7 protein destabilizes p130, a pRb-related pocket protein, thereby promoting S-phase reentry in postmitotic, differentiated keratinocytes of squamous epithelia, and that HR HPV E7 does so more efficiently than LR HPV E7. The E7 proteins of LR HPV-11 and -6b uniquely possess lysine residues following a casein kinase II phosphorylation motif which is critical for the biological function of E7. We now show that mutations of these lysine residues elevated the efficiency of S-phase reentry, independent of their charge. An 11E7 K39,42R mutation moderately increased the association with and the destabilization of p130. Unexpectedly, polyubiquitination on these lysine residues did not attenuate E7 activity, as their mutation caused elevated proteasomal degradation and decreased protein stability. In this regard, the biologically more potent HR HPV E7 proteins were also less stable than the LR HPV E7 proteins. We infer that these lysine residues impede functional protein-protein interactions. A G22D mutation of 11E7 at the pocket protein binding motif possessed augmented efficiency in promoting S-phase reentry and strongly enhanced association with p130 and pRb. The combined effects of these two classes of 11E7 mutations exhibited an efficiency of S-phase reentry comparable to that of HR HPV E7. Thus, these nonconserved residues are primarily responsible for the differential abilities of LR and HR HPV E7 proteins to promote unscheduled DNA replication in organotypic raft cultures.The human papillomavirus (HPV) genome amplifies in suprabasal, differentiated keratinocytes as extrachromosomal plasmids. Viral DNA replication requires the host DNA replication proteins. The normal squamous epithelium is, however, postmitotic and nonsupportive of viral DNA amplification. After asymmetrical cell division from the proliferative basal and transit amplifying compartments, cell cycle reentry by differentiated keratinocytes is permanently repressed by retinoblastoma family pocket proteins. Pocket proteins p130 and pRb repress cell cycle entry by regulation of the E2F family of transcription factors (for a review, see reference 54). During the keratinocyte differentiation process, the pRb expression level decreases while that of p130 increases, implying a dominant role for p130 in repressing cell cycle entry in the postmitotic epithelium (19,43,65). The HPV E7 protein inactivates p130, thereby evoking cell cycle entry permissive for amplification of the viral genome. Our recent study demonstrated that viral genome amplification occurs in spinous cells arrested in a prolonged G 2 state in the absence of competition from host DNA replication (3a, 59).Mucosotrophic HPV types of the Alphapapillomavirus genus are classified as low risk (LR; e.g., types 6b and 11) or high risk (HR; e.g., types 16 and 18), according to the potential of the infections to pro...

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Section: Discussionmentioning

confidence: 99%

Nonconserved Lysine Residues Attenuate the Biological Function of the Low-Risk Human Papillomavirus E7 Protein

Genovese

Broker

Chow

2011

J Virol

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“…This is a rather small interface for a stable protein dimer (Yan et al, 2008). Lattice contacts revealed another possible dimer in the crystal with a larger buried surface area (498 Å 2 ; not shown), but the C-termini of the molecules in this dimer point in opposite directions so that it is exceedingly unlikely that they could simultaneously cross the inner membrane.…”

mentioning

confidence: 94%

Structure of the cytoplasmic domain ofYersinia pestisYscD, an essential component of the type III secretion system

Lountos

Tropea

Waugh

2012

Acta Crystallogr D Biol Cryst

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The Yersinia pestis YscD protein is an essential component of the type III secretion system. YscD consists of an N-terminal cytoplasmic domain (residues 1-121), a transmembrane linker (122-142) and a large periplasmic domain (143-419). Both the cytoplasmic and the periplasmic domains are required for the assembly of the type III secretion system. Here, the structure of the YscD cytoplasmic domain solved by SAD phasing is presented. Although the three-dimensional structure is similar to those of forkhead-associated (FHA) domains, comparison with the structures of canonical FHA domains revealed that the cytoplasmic domain of YscD lacks the conserved residues that are required for binding phosphothreonine and is therefore unlikely to function as a true FHA domain.

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“…The results suggest that refining the predictions generated by the voting scheme based on the clustering tendency of the interface residues further improves the quality of predictions. These results suggest the possibility of using structural properties of interfaces to improve the quality of protein-protein interface residue prediction beyond that of sequence-based prediction methods [24,25].…”

Section: Discussionmentioning

confidence: 98%