An analysis of side chain interactions and pair correlations within antiparallel β‐sheets: The differences between backbone hydrogen‐bonded and non‐hydrogen‐bonded residue pairs

Wouters, Merridee A.; Curmi, Paul M. G.

doi:10.1002/prot.340220205

Cited by 241 publications

(288 citation statements)

References 24 publications

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“…The sequences of G5 and E domains show a high content of long charged residues (Glu, ∼15%; and Lys, ∼15%), and analysis of the E-G5 2 and G5 1 -E-G5 2 crystal structures reveal that short nonpolar side chains (Ala, Val, Ile, Leu) form small hydrophobic clusters surrounded by large hydrophilic amino acids. In addition, the long, charged side chains form cross-strand arrays of alternating charges observed previously in antiparallel β-sheets (36).…”

Section: Discussionmentioning

confidence: 52%

Staphylococcal biofilm-forming protein has a contiguous rod-like structure

Gruszka

Wojdyla

Bingham

et al. 2012

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

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Staphylococcus aureus and Staphylococcus epidermidis form communities (called biofilms) on inserted medical devices, leading to infections that affect many millions of patients worldwide and cause substantial morbidity and mortality. As biofilms are resistant to antibiotics, device removal is often required to resolve the infection. Thus, there is a need for new therapeutic strategies and molecular data that might assist their development. Surface proteins S. aureus surface protein G (SasG) and accumulation-associated protein ( S. epidermidis ) promote biofilm formation through their “B” regions. B regions contain tandemly arrayed G5 domains interspersed with approximately 50 residue sequences (herein called E) and have been proposed to mediate intercellular accumulation through Zn 2+ -mediated homodimerization. Although E regions are predicted to be unstructured, SasG and accumulation-associated protein form extended fibrils on the bacterial surface. Here we report structures of E–G5 and G5–E–G5 from SasG and biophysical characteristics of single and multidomain fragments. E sequences fold cooperatively and form interlocking interfaces with G5 domains in a head-to-tail fashion, resulting in a contiguous, elongated, monomeric structure. E and G5 domains lack a compact hydrophobic core, and yet G5 domain and multidomain constructs have thermodynamic stabilities only slightly lower than globular proteins of similar size. Zn 2+ does not cause SasG domains to form dimers. The work reveals a paradigm for formation of fibrils on the 100-nm scale and suggests that biofilm accumulation occurs through a mechanism distinct from the “zinc zipper.” Finally, formation of two domains by each repeat (as in SasG) might reduce misfolding in proteins when the tandem arrangement of highly similar sequences is advantageous.

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Section: Discussionmentioning

confidence: 52%

Staphylococcal biofilm-forming protein has a contiguous rod-like structure

Gruszka

Wojdyla

Bingham

et al. 2012

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

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“…In our calculation, we assume the canonical strand interaction model (15,17,26,27) (also see SI Appendix) and require only knowledge of the start position of the TM strands. Because the amount of required structural information is very small, our method can also predict oligomerization state and identify the interface for protein-protein interaction by using sequence information only.…”

Section: Prediction Of Oligomerization State and Interface For Proteimentioning

confidence: 99%

Predicting weakly stable regions, oligomerization state, and protein–protein interfaces in transmembrane domains of outer membrane proteins

Naveed

Jackups

Liang

2009

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

109

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Although the structures of many ␤-barrel membrane proteins are available, our knowledge of the principles that govern their energetics and oligomerization states is incomplete. Here we describe a computational method to study the transmembrane (TM) domains of ␤-barrel membrane proteins. Our method is based on a physical interaction model, a simplified conformational space for efficient enumeration, and an empirical potential function from a detailed combinatorial analysis. Using this method, we can identify weakly stable regions in the TM domain, which are found to be important structural determinants for ␤-barrel membrane proteins. By calculating the melting temperatures of the TM strands, our method can also assess the stability of ␤-barrel membrane proteins. Predictions on membrane enzyme PagP are consistent with recent experimental NMR and mutant studies. We have also discovered that out-clamps, in-plugs, and oligomerization are 3 general mechanisms for stabilizing weakly stable TM regions. In addition, we have found that extended and contiguous weakly stable regions often signal the existence of an oligomer and that strands located in the interfaces of protein-protein interactions are considerably less stable. Based on these observations, we can predict oligomerization states and can identify the interfaces of protein-protein interactions for ␤-barrel membrane proteins by using either structure or sequence information. In a set of 25 nonhomologous proteins with known structures, our method successfully predicted whether a protein forms a monomer or an oligomer with 91% accuracy; in addition, our method identified with 82% accuracy the protein-protein interaction interfaces by using sequence information only when correct strands are given.in-plug ͉ membrane protein oligomerization ͉ out-clamp ͉ protein-protein interaction ͉ weakly stable TM strand D eveloping a general understanding of how proteins behave in membranes is of fundamental importance. ␤-barrel membrane proteins, one of the 2 major structural classes of membrane proteins, have been studied extensively. Currently, structures of 70 ␤-barrel membrane proteins have been resolved, and much has been learned about their thermodynamic stability (1), folding kinetics (2-4), biogenesis (5), and biological functions (6). These membrane proteins are thought to have very regular structures, with the basic principles of their architectural organization well understood (7). An overwhelming structural feature is the existence of an extensive regular hydrogen bond network between the transmembrane (TM) ␤-strands, which is thought to confer extreme stability on the proteins (8).However, ␤-barrel membrane proteins have diverse structures and often deviate significantly from the standard barrel architecture. For example, there are often small ␣-helices and ␤-strands, called in-plugs, found inside the ␤-barrel (9). Nonbarrel-embedded helices are also found to pack against the TM ␤-strands (10). In addition, some ␤-barrel membrane proteins exist in monomeric form, whe...

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“…25 We used the statistical correlation data because experimental thermodynamic data is available only for a small number of cross-strand pair types. 18 No significant overall correlation was found (r = −0.22; Fig 3B).…”

Section: Contributions Of Cross-strand Pairwise Interactionsmentioning

confidence: 99%

Hydrophobic Surface Burial Is the Major Stability Determinant of a Flat, Single-layer β-Sheet

Yan¹,

Gawlak²,

Makabe³

et al. 2007

Journal of Molecular Biology

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Formation of a flat β-sheet is a fundamental event in β-sheet-mediated protein self-assembly. To investigate contributions of various factors to the stability of flat β-sheets, we performed extensive alanine-scanning mutagenesis experiments on the single-layer β-sheet segment of Borrelia outer surface protein A (OspA). This β-sheet segment consists of β-strands with highly regular geometries that can serve as a building block for self-assembly. Our Ala-scanning approach is distinct from the conventional host-guest method in that it introduces only conservative, truncation mutations that should minimize structural perturbation. Our results showed very weak correlation with experimental β-sheet propensity scales, statistical β-sheet propensity scales, or cross-strand pairwise correlations. In contrast, our data showed strong positive correlation with the change in buried nonpolar surface area. Polar interactions including prominent Glu-Lys cross-strand pairs marginally contribute to the β-sheet stability. These results were corroborated by results from additional non-Ala mutations. Taken together, these results demonstrate the dominant contribution of nonpolar surface burial to flat β-sheet stability even at solvent-exposed positions. The OspA single-layer β-sheet achieves efficient hydrophobic surface burial without forming a hydrophobic core by a strategic placement of a variety of side chains. These findings further suggest the importance of hydrophobic interactions within a β-sheet layer in peptide self-assembly.

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An analysis of side chain interactions and pair correlations within antiparallel β‐sheets: The differences between backbone hydrogen‐bonded and non‐hydrogen‐bonded residue pairs

Cited by 241 publications

References 24 publications

Staphylococcal biofilm-forming protein has a contiguous rod-like structure

Staphylococcal biofilm-forming protein has a contiguous rod-like structure

Predicting weakly stable regions, oligomerization state, and protein–protein interfaces in transmembrane domains of outer membrane proteins

Hydrophobic Surface Burial Is the Major Stability Determinant of a Flat, Single-layer β-Sheet

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