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Post-translational modifications (PTMs) represent an important regulatory instrument that modulates structure, dynamics and function of proteins. The large number of PTM sites in the Hsp90 proteins that are scattered throughout different domains indicated that synchronization of multiple PTMs through a combinatorial code can be invoked as an important mechanism to orchestrate diverse chaperone functions and recognize multiple client proteins. In this study, we have combined structural and coevolutionary analysis with molecular simulations and perturbation response scanning analysis of the Hsp90 structures to characterize functional role of PTM sites in allosteric regulation. The results reveal a small group of conserved PTMs that act as global mediators of collective dynamics and allosteric communications in the Hsp90 structures, while the majority of flexible PTM sites serve as sensors and carriers of the allosteric structural changes. This study provides a comprehensive structural, dynamic and network analysis of PTM sites across Hsp90 proteins, identifying specific role of regulatory PTM hotspots in the allosteric mechanism of the Hsp90 cycle. We argue that plasticity of a combinatorial PTM code in the Hsp90 may be enacted through allosteric coupling between effector and sensor PTM residues, which would allow for timely response to structural requirements of multiple modified enzymes.
Pubmed ID: 29720613
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A freely accessible on-line systems biology resource devoted to all aspects of protein modification, as well as other post-translational modifications. It provides valuable and unique tools for both cell biologists and mass spectroscopists. PhosphoSite is a human- and mouse-centric database. It includes features such as: viewing the locations of modified residues on molecular models; browsing and searching MS2 records by disease, tissue, and cell line; submitting lists of peptides to identify previously reported genes; searching by sub-cellular localization, treatment, tissues, cell types, cell lines and diseases, and protein types and protein domains; searching for experimentally-verified kinase substrates and viewing preferred substrate motifs; and viewing MS2 spectra for peptides and sites not previously published.
View all literature mentionsTool for searching sequence databases for homologs of protein sequences, and for making protein sequence alignments. It implements methods using probabilistic models called profile hidden Markov models (profile HMMs). Compared to BLAST, FASTA, and other sequence alignment and database search tools based on older scoring methodology, HMMER aims to be significantly more accurate and more able to detect remote homologs because of the strength of its underlying mathematical models. In the past, this strength came at significant computational expense, but in the new HMMER3 project, HMMER is now essentially as fast as BLAST.
View all literature mentionsCentral repository for collection of functional information on proteins, with accurate and consistent annotation. In addition to capturing core data mandatory for each UniProtKB entry (mainly, the amino acid sequence, protein name or description, taxonomic data and citation information), as much annotation information as possible is added. This includes widely accepted biological ontologies, classifications and cross-references, and experimental and computational data. The UniProt Knowledgebase consists of two sections, UniProtKB/Swiss-Prot and UniProtKB/TrEMBL. UniProtKB/Swiss-Prot (reviewed) is a high quality manually annotated and non-redundant protein sequence database which brings together experimental results, computed features, and scientific conclusions. UniProtKB/TrEMBL (unreviewed) contains protein sequences associated with computationally generated annotation and large-scale functional characterization that await full manual annotation. Users may browse by taxonomy, keyword, gene ontology, enzyme class or pathway.
View all literature mentionsA database of protein families, each represented by multiple sequence alignments and hidden Markov models (HMMs). Users can analyze protein sequences for Pfam matches, view Pfam family annotation and alignments, see groups of related families, look at the domain organization of a protein sequence, find the domains on a PDB structure, and query Pfam by keywords. There are two components to Pfam: Pfam-A and Pfam-B. Pfam-A entries are high quality, manually curated families that may automatically generate a supplement using the ADDA database. These automatically generated entries are called Pfam-B. Although of lower quality, Pfam-B families can be useful for identifying functionally conserved regions when no Pfam-A entries are found. Pfam also generates higher-level groupings of related families, known as clans (collections of Pfam-A entries which are related by similarity of sequence, structure or profile-HMM).
View all literature mentionsParallel molecular dynamics code designed for high-performance simulation of large biomolecular systems. NAMD uses the popular molecular graphics program VMD for simulation setup and trajectory analysis, but is also file-compatible with AMBER, CHARMM, and X-PLOR.
View all literature mentionsSoftware tool as Program for Comparative Protein Structure Modelling by Satisfaction of Spatial Restraints. Used for homology or comparative modeling of protein three dimensional structures. User provides alignment of sequence to be modeled with known related structures and MODELLER automatically calculates model containing all non hydrogen atoms.
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