Turn up the HEAT

Kobe, Boštjan; Gleichmann, T.; Horne, James; Jennings, Ian G.; Scotney, Pierre D; Teh, Trazel

doi:10.1016/s0969-2126(99)80060-4

Cited by 65 publications

(58 citation statements)

References 43 publications

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“…1 A. Overall it is clear that the phantom ⌿(A, B) and ⌽(A, B) long-range adaptive patterns of the helical arms of PR65/A, shown in Fig. 1, provide a better interpretation of the locations and functions of the heterotrimer protein interfaces (20) than the interrepeat spatial patterns (18,19) of isolated PR65/A. The hydroflexibility of the helical arms enables the intrarepeat loops, which are in close proximity to the regulatory B and catalytic C subunits (20), to adopt optimal conformations.…”

Section: Scaffolding Heat Proteinmentioning

confidence: 89%

“…The A arms are associated with the exposed convex outer surface, whereas the B arms belong to the concave inner surface, which functions as the scaffolding support for catalytic and regulatory domains in the tumor suppressor protein phosphatase PP2A (18,20,21).…”

Section: Scaffolding Heat Proteinmentioning

confidence: 99%

“…However, at the same time the aberrant nonparallel packing between repeats 3 and 4, and 12 and 13, apparently caused by divergences from the consensus sequence, probably reflect only the marginal stability of isolated PR65/A. These ''breaks'' received detailed attention in discussions of the isolated structure, including many amino acid-specific packing interactions (18,19), but they appear to be irrelevant to the heterotrimer interfaces, which, of course, are tailored by functionality and stabilized in the complex. The break at repeat 12 disappears in the heterotrimeric structure, in which the overall shape of PR65/A changes from a twisted hook to a more regular horseshoe (20).…”

Section: Scaffolding Heat Proteinmentioning

confidence: 99%

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Scaling and self-organized criticality in proteins I

Phillips

2009

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

100

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The complexity of proteins is substantially simplified by regarding them as archetypical examples of self-organized criticality (SOC). To test this idea and elaborate on it, this article applies the Moret-Zebende SOC hydrophobicity scale to the large-scale scaffold repeat protein of the HEAT superfamily, PR65/A. Hydrophobic plasticity is defined and used to identify docking platforms and hinges from repeat sequences alone. The difference between the MZ scale and conventional hydrophobicity scales reflects longrange conformational forces that are central to protein functionality.hydrophobicity ͉ repeat ͉ scaling T here are many scales (hydrophobicity, charge, helix-forming propensity, etc.) that bioinformatically describe various aspects of amino acid interactions in proteins and their relations to sequence, structure, stability, and functionality, all justified by combining plausible constructs with parameters adjusted through statistical searches. Are all such scales equally useful, and are the substantial differences among them attributable to their inevitably heuristic character? Here, I discuss differences in methodology, with special emphasis on holistic vs. reductionist approaches. I suggest that a better understanding of the limitations and potential of scaling analysis of proteins will result from systematic studies of simple cases first, such as repeat proteins and their associates. Scaling analysis may prove to be a valuable tool in designing proteins with desired functions.Many physical systems exhibit power-law distributions over limited ranges (hence the popularity of log-log graph paper), and power-law distributions are the characteristic feature of the modern theory of phase transitions near a critical point. Self-organized criticality (SOC) is a methodology that attempts to explain why so many complex systems exhibit power-law distributions and appear to be ''accidentally'' located near critical points. It is argued that the critical points are dynamical fixed points (''tipping points'') toward which the system evolves without tuning external parameters (1). The critical points are extrema in some property (or properties) with respect to which the system has been optimized, especially with respect to long-range, highly-cooperative interactions, such as conformational changes.Given the widespread occurrence of power laws, SOC has great intuitive appeal: it has achieved an enduring popularity among theorists (Ͼ2,500 papers discussing SOC, Ͼ25 current books from a single publisher), notably in modeling the critical stability of sand piles against avalanches, but its concrete applications have been limited largely to seismic phenomena. A cautionary remark: power laws, especially in the context of dissipative reactions, have often been interpreted in terms of SOC, but a simpler interpretation involves only slow sweeping of a control parameter toward a global extremal, as could occur in the context of commercial product optimization (2). However, more recently Boolchand and coworkers (3) discovered a r...

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Section: Scaffolding Heat Proteinmentioning

confidence: 89%

Section: Scaffolding Heat Proteinmentioning

confidence: 99%

Section: Scaffolding Heat Proteinmentioning

confidence: 99%

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Scaling and self-organized criticality in proteins I

Phillips

2009

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

100

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“…Importin ␤ presents a modular structure built of 19 tandem HEAT repeats (10). Each HEAT repeat is a simple secondary structural motif formed by two helices (A and B) connected by a short loop (11,12). In the tertiary structure of importin ␤, 19 HEAT repeats are arranged to form a superhelix of helices, which exposes two structurally and functionally distinct surfaces to the solvent (10).…”

mentioning

confidence: 99%

Phospholipid Scramblase 1 Contains a Nonclassical Nuclear Localization Signal with Unique Binding Site in Importin α

Chen

Ben-Efraim

Mitrousis

et al. 2005

Journal of Biological Chemistry

100

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Nuclear import of proteins containing a classical nuclear localization signal (NLS) is an energy-dependent process that requires the heterodimer importin ␣/␤.Three to six basic contiguous arginine/lysine residues characterize a classical NLS and are thought to form a basic patch on the surface of the import cargo. In this study, we have characterized the NLS of phospholipid scramblase 1 (PLSCR1), a lipid-binding protein that enters the nucleus via the nonclassical NLS 257 GKISKH-WTGI 266 . This import sequence lacks a contiguous stretch of positively charged residues, and it is enriched in hydrophobic residues. We have determined the 2.2 Å crystal structure of a complex between the PLSCR1 NLS and the armadillo repeat core of vertebrate importin ␣. Our crystallographic analysis reveals that PLSCR1 NLS binds to armadillo repeats 1-4 of importin ␣, but its interaction partially overlaps the classical NLS binding site. Two PLSCR1 lysines occupy the canonical positions indicated as P2 and P5. Moreover, we present in vivo evidence that the critical lysine at position P2, which is essential in other known NLS sequences, is dispensable in PLSCR1 NLS. Taken together, these data provide insight into a novel nuclear localization signal that presents a distinct motif for binding to importin ␣.Nuclear transport is an active signal-mediated process that requires, in most cases, soluble transport factors and specific import signals. Two families of transport receptors have been identified in the importin ␤ superfamily, which is involved in both nuclear import and export, and the TAP superfamily that mediates nuclear export. Transport receptors recognize specific nuclear localization signals (NLSs) 1 and nuclear export signals exposed on the molecular surface of cargoes. In the classical nuclear import pathway proteins bearing a classical SV40-like NLS (PKKKRKV) are recognized by the importin ␣/␤ heterodimer (also known as karyopherin ␣/␤) (1-3). Importin ␣ (4) acts as an adaptor that recognizes NLS sequences after association with the receptor importin ␤ (5). The importin ␣/␤-NLS cargo complex is then translocated through the nuclear pore complex in a process that requires multiple rounds of interaction of the receptor importin ␤ with nucleoporins, likely via their exposed hydrophobic FG-rich motifs (6, 7

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“…1D) constrains the HEAT repeat structure, thereby, forcing it to take such a peculiar curvature. 71,72 Bias in the fitting of the SF3b155 model to the cryo-EM data is low due to the reasons mentioned above. Hence, our approach of fragment-based fitting and refinement by flexible fitting, has allowed us to assign the HEAT repeats in the density with reasonable confidence and obtain insights into the SF3b155 structure (Fig.…”

Section: Sf3b155 -A Highly Curved Heat Repeat Proteinmentioning

confidence: 99%

Structural and mechanistic insights into human splicing factor SF3b complex derived using an integrated approach guided by the cryo-EM density maps

et al. 2016

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Pre-mRNA splicing in eukaryotes is performed by the spliceosome, a highly complex macromolecular machine. SF3b is a multi-protein complex which recognizes the branch point adenosine of pre-mRNA as part of a larger U2 snRNP or U11/U12 di-snRNP in the dynamic spliceosome machinery. Although a cryo-EM map is available for human SF3b complex, the structure and relative spatial arrangement of all components in the complex are not yet known. We have recognized folds of domains in various proteins in the assembly and generated comparative models. Using an integrative approach involving structural and other experimental data, guided by the available cryo-EM density map, we deciphered a pseudoatomic model of the closed form of SF3b which is found to be a "fuzzy complex" with highly flexible components and multiplicity of folds. Further, the model provides structural information for 5 proteins (SF3b10, SF3b155, SF3b145, SF3b130 and SF3b14b) and localization information for 4 proteins (SF3b10, SF3b145, SF3b130 and SF3b14b) in the assembly for the first time. Integration of this model with the available U11/U12 di-snRNP cryo-EM map enabled elucidation of an open form. This now provides new insights on the mechanistic features involved in the transition between closed and open forms pivoted by a hinge region in the SF3b155 protein that also harbors cancer causing mutations. Moreover, the open form guided model of the 5 0 end of U12 snRNA, which includes the branch point duplex, shows that the architecture of SF3b acts as a scaffold for U12 snRNA: pre-mRNA branch point duplex formation with potential implications for branch point adenosine recognition fidelity.

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Turn up the HEAT

Cited by 65 publications

References 43 publications

Scaling and self-organized criticality in proteins I

Scaling and self-organized criticality in proteins I

Phospholipid Scramblase 1 Contains a Nonclassical Nuclear Localization Signal with Unique Binding Site in Importin α

Structural and mechanistic insights into human splicing factor SF3b complex derived using an integrated approach guided by the cryo-EM density maps

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