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Song W.J.,University of California at San Diego | Sontz P.A.,University of California at San Diego | Ambroggio X.I.,Rosetta Design Group LLC | Tezcan F.A.,University of California at San Diego
Annual Review of Biophysics | Year: 2014

From the catalytic reactions that sustain the global oxygen, nitrogen, and carbon cycles to the stabilization of DNA processing proteins, transition metal ions and metallocofactors play key roles in biology. Although the exquisite interplay between metal ions and protein scaffolds has been studied extensively, the fact that the biological roles of the metals often stem from their placement in the interfaces between proteins and protein subunits is not always recognized. Interfacial metal ions stabilize permanent or transient protein-protein interactions, enable protein complexes involved in cellular signaling to adopt distinct conformations in response to environmental stimuli, and catalyze challenging chemical reactions that are uniquely performed by multisubunit protein complexes. This review provides a structural survey of transition metal ions and metallocofactors found in protein-protein interfaces, along with a series of selected examples that illustrate their diverse biological utility and significance. Copyright © 2014 by Annual Reviews. All rights reserved. Source


Brodin J.D.,University of California at San Diego | Ambroggio X.I.,Rosetta Design Group LLC | Tang C.,University of California at San Diego | Parent K.N.,University of California at San Diego | And 2 more authors.
Nature Chemistry | Year: 2012

Proteins represent the most sophisticated building blocks available to an organism and to the laboratory chemist. Yet, in contrast to nearly all other types of molecular building blocks, the designed self-assembly of proteins has largely been inaccessible because of the chemical and structural heterogeneity of protein surfaces. To circumvent the challenge of programming extensive non-covalent interactions to control protein self-assembly, we have previously exploited the directionality and strength of metal coordination interactions to guide the formation of closed, homoligomeric protein assemblies. Here, we extend this strategy to the generation of periodic protein arrays. We show that a monomeric protein with properly oriented coordination motifs on its surface can arrange, on metal binding, into one-dimensional nanotubes and two- or three-dimensional crystalline arrays with dimensions that collectively span nearly the entire nano- and micrometre scale. The assembly of these arrays is tuned predictably by external stimuli, such as metal concentration and pH. © 2012 Macmillan Publishers Limited. All rights reserved. Source


Brodin J.D.,University of California at San Diego | Medina-Morales A.,University of California at San Diego | Ni T.,University of California at San Diego | Salgado E.N.,University of California at San Diego | And 2 more authors.
Journal of the American Chemical Society | Year: 2010

Selective binding by metalloproteins to their cognate metal Ions is essential to cellular survival. How proteins originally acquired the ability to selectively bind metals and evolved a diverse array of metalcentered functions despite the availability of only a few metal-coordinating functionalities remains an open question. Using a rational design approach (Metal-Templated Interface Redesign), we describe the transformation of a monomeric electron transfer protein, cytochrome cb562, into a tetrameric assembly ( C96RIDC-14) that stably and selectively binds Zn 2+ and displays a metal-dependent conformational change reminiscent of a signaling protein. A thorough analysis of the metal binding properties ofC96RIDC-14 reveals that It can also stably harbor other divalent metals with affinities that rival (Ni2+) or even exceed (Cu2+) those of Zn2+ on a per site basis. Nevertheless, this analysis suggests that our templating strategy simultaneously introduces an increased bias toward binding a higher number of Zn2+ ions (four high affinity sites) versus Cu2+ or Ni2+ (two high affinity sites), ultimately leading to the exclusive selectivity of C96RIDC14 for Zn2+ over those ions. More generally, our results indicate that an initial metal-driven nucleation event followed by the formation of a stable protein architecture around the metal provides a straightforward path for generating structural and functional diversity. © 2010 American Chemical Society. Source


Moslehi R.,University at Albany | Ambroggio X.,Rosetta Design Group LLC | Nagarajan V.,U.S. National Institutes of Health | Kumar A.,University at Albany | And 2 more authors.
BMC Genomics | Year: 2014

Background: Preeclampsia is a significant cause of maternal and fetal mortality and morbidity worldwide. We previously reported associations between trichothiodystrophy (TTD) nucleotide excision repair (NER) and transcription gene mutations in the fetus and the risk of gestational complications including preeclampsia. TTD NER/transcription genes, XPD, XPB and TTD-A, code for subunits of Transcription Factor (TF)IIH. Interpreting XPD mutations in the context of available biochemical data led us to propose adverse effects on CDK-activating kinase (CAK) subunit of TFIIH and TFIIH-mediated functions as a relevant mechanism in preeclampsia. In order to gain deeper insight into the underlying biologic mechanisms involving TFIIH-mediated functions in placenta, we analyzed NER/transcription and global gene expression profiles of normal and preeclamptic placentas and studied gene regulatory networks.Results: We found high expression of TTD NER/transcription genes in normal human placenta, above the mean of their expression in all organs. XPD and XPB were consistently expressed from 14 to 40 weeks gestation while expression of TTD-A was strongly negatively correlated (r = -0.7, P < 0.0001) with gestational age. Analysis of gene expression patterns of placentas from a case-control study of preeclampsia using Algorithm for Reconstruction of Accurate Cellular Networks (ARACNE) revealed GTF2E1, a component of TFIIE which modulates TFIIH, among major regulators of differentially-expressed genes in preeclampsia. The basal transcription pathway was among the largest dysregulated protein-protein interaction networks in this preeclampsia dataset. Within the basal transcription pathway, significantly down-regulated genes besides GTF2E1 included those coding for the CAK complex of TFIIH, namely CDK7, CCNH, and MNAT1. Analysis of other relevant gene expression and gene regulatory network data also underscored the involvement of transcription pathways and identified JUNB and JUND (components of transcription factor AP-1) as transcription regulators of the network involving the TTD genes, GTF2E1, and selected gene regulators implicated in preeclampsia.Conclusions: Our results indicate that TTD NER/transcription genes are expressed in placenta during gestational periods critical to preeclampsia development. Our overall findings suggest that impairment of TFIIH-mediated function in transcription in placenta is a likely mechanism leading to preeclampsia and provide etiologic clues which may be translated into therapeutic and preventive measures. © 2014 Moslehi et al.; licensee BioMed Central Ltd. Source


London N.,Rosetta Design Group LLC | London N.,University of California at San Francisco | Ambroggio X.,Rosetta Design Group LLC
Journal of Structural Biology | Year: 2014

Computational protein design efforts aim to create novel proteins and functions in an automated manner and, in the process, these efforts shed light on the factors shaping natural proteins. The focus of these efforts has progressed from the interior of proteins to their surface and the design of functions, such as binding or catalysis. Here we examine progress in the development of robust methods for the computational design of non-natural interactions between proteins and molecular targets such as other proteins or small molecules. This problem is referred to as the de novo computational design of interactions. Recent successful efforts in de novo enzyme design and the de novo design of protein-protein interactions open a path towards solving this problem. We examine the common themes in these efforts, and review recent studies aimed at understanding the nature of successes and failures in the de novo computational design of interactions. While several approaches culminated in success, the use of a well-defined structural model for a specific binding interaction in particular has emerged as a key strategy for a successful design, and is therefore reviewed with special consideration. © 2013 Elsevier Inc. Source

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