Native-like and structurally characterized designed α-helical bundles

Betz, Stephen F.; Bryson, James W.; DeGrado, William F.

doi:10.1016/0959-440x(95)80029-8

Cited by 108 publications

(93 citation statements)

References 34 publications

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“…[46][47][48][49] With the exception of the most frustrated system, the curves for the other systems considered (ASF1, AF, AUF1, and AUF2) exhibit sigmoidal shapes in qualitative agreement with experimental thermal denaturation curves obtained from protein design experiments.…”

Section: Resultssupporting

confidence: 65%

Sequence periodicity and secondary structure propensity in model proteins

2010

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We explore the question of whether local effects (originating from the amino acids intrinsic secondary structure propensities) or nonlocal effects (reflecting the sequence of amino acids as a whole) play a larger role in determining the fold of globular proteins. Earlier circular dichroism studies have shown that the pattern of polar, non polar amino acids (nonlocal effect) dominates over the amino acid intrinsic propensity (local effect) in determining the secondary structure of oligomeric peptides. In this article, we present a coarse grained computational model that allows us to quantitatively estimate the role of local and nonlocal factors in determining both the secondary and tertiary structure of small, globular proteins. The amino acid intrinsic secondary structure propensity is modeled by a dihedral potential term. This dihedral potential is parametrized to match with experimental measurements of secondary structure propensity. Similarly, the magnitude of the attraction between hydrophobic residues is parametrized to match the experimental transfer free energies of hydrophobic amino acids. Under these parametrization conditions, we systematically explore the degree of frustration a given polar, non polar pattern can tolerate when the secondary structure intrinsic propensities are in opposition to it. When the parameters are in the biophysically relevant range, we observe that the fold of small, globular proteins is determined by the pattern of polar, non polar amino acids regardless of their instrinsic secondary structure propensities. Our simulations shed new light on previous observations that tertiary interactions are more influential in determining protein structure than secondary structure propensity. The fact that this can be inferred using a simple polymer model that lacks most of the biochemical details points to the fundamental importance of binary patterning in governing folding.

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Section: Resultssupporting

confidence: 65%

Sequence periodicity and secondary structure propensity in model proteins

2010

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“…It has been reported to be more stable and better than V and L at this position in conferring dimers (12,13). FosW L and I were selected over V in all four instances, despite a documented ␤-over ␥-branching preference (12,38). V alone yields trimers (39) or a mixture of dimers and trimers (12), whereas I can specify dimers exclusively.…”

Section: Discussionmentioning

confidence: 99%

Semirational design of Jun-Fos coiled coils with increased affinity: Universal implications for leucine zipper prediction and design

Mason

Schmitz

Müller

et al. 2006

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

127

287

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Finally, and with wider implications, we have compiled a method for predicting interaction of parallel, dimeric coiled coils, using our T m data as a training set, and applying it to 59 bZIP proteins previously reported. Our algorithm, unlike others to date, accounts for helix propensity, which is found to be integral in coiled coil stability. Indeed, in applying the algorithm to these 59 2 bZIP interactions, we were able to correctly identify 92% of all strong interactions and 92% of all noninteracting pairs.bioinformatics ͉ protein design ͉ protein stability ͉ protein-protein interaction ͉ dominant negative T he dimeric transcription factor activator protein-1 (AP-1) comprises Jun, Fos, activating transcription factor, and musculoaponeurotic fibrosarcoma families. Chief mammalian cell AP-1 constituents, Jun and Fos, contain a transactivation domain, a basic region for recognizing a DNA consensus sequence and a leucine zipper [coiled coil (CC)] region (see Fig. 1). The latter, in dimerizing, permits the two basic domains to bind to their consensus sequence. Such transcription factors, known as basic-zipper or bZIP proteins, are found at the closing stages of mitogen-activated protein kinase signaling cascades (e.g., the RAS pathway). AP-1 is implicated in various cancers where it can become up-regulated or overexpressed (1), and has been shown to be important in cell growth initiation, with c-Jun and c-Fos identified as cellular counterparts to viral oncoproteins v-Jun and v-Fos, thus establishing their role in tumorigenesis (2). Indeed, they are central in numerous oncogenic pathways and could therefore be prime candidates in anticancer drug design. However, AP-1 can also have antiproliferative properties, depending on subunit composition, transcription level, posttranslational modification (e.g., phosphorylation), and interaction with other proteins (e.g., Jun N-terminal kinase); this is manifested by the preponderance of different AP-1 family members in different types of tissue cancer. . Alternative residue options were included at e and g positions, and were aimed at varying electrostatic attraction levels at the dimeric interface. Other alternative residues, largely taken from homologues (see key), were introduced to the library pool at the solvent exposed b, c, and f positions. Wild-type residues removed from libraries are struck through in green, newly introduced amino acids are marked red, and wildtype positions left in the library are marked blue. Library winner selections are circled green. Position c1 E (marked red) is for additional N-cap stability, whereas b3 Y assists with concentration determination. Capping motifs have also been added.

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“…Coiled coils offer attractive features to the protein designer and were among the first rationally designed structures [3]. Hydrophobic-polar patterning imposes association of helices, and charge patterning and other features can be used to confer specificity.…”

Section: Introductionmentioning

confidence: 99%

Structural specificity in coiled-coil interactions

Grigoryan

Keating

2008

Current Opinion in Structural Biology

266

283

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Coiled coils have a rich history in the field of protein design and engineering. Novel structures, such as the first 7-helix coiled coil, continue to provide surprises and insights. Large-scale data sets quantifying the influence of systematic mutations on coiled-coil stability are a valuable new asset to the area. Scoring methods based on sequence and/or structure can predict interaction preferences in coiled-coil-mediated bZIP transcription factor dimerization. Experimental and computational methods for dealing with the near-degeneracy of many coiled-coil structures appear promising for future design applications.

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Native-like and structurally characterized designed α-helical bundles

Cited by 108 publications

References 34 publications

Sequence periodicity and secondary structure propensity in model proteins

Sequence periodicity and secondary structure propensity in model proteins

Semirational design of Jun-Fos coiled coils with increased affinity: Universal implications for leucine zipper prediction and design

Structural specificity in coiled-coil interactions

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