Targeting disorders in unstructured and structured proteins in various diseases

2021 ◽  
pp. 106742
Author(s):  
Sinjan Choudhary ◽  
Manu Lopus ◽  
Ramakrishna V. Hosur
Keyword(s):  
Structured Proteins

Nonnative contact effects in protein folding

2019 ◽  
Vol 21 (22) ◽  
pp. 11924-11936 ◽  
Author(s):  
Qiang Shao ◽  
Weiliang Zhu
Keyword(s):  
Protein Folding ◽  
Folding Simulations ◽  
Structured Proteins ◽  
Contact Effects

The folding simulations of three ββα-motifs and β-barrel structured proteins (NTL9, NuG2b, and CspA) were performed to determine the important roles of native and nonnative contacts in protein folding.

scholarly journals Genetically tunable frustration controls allostery in an intrinsically disordered transcription factor

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jing Li ◽  
Jordan T White ◽  
Harry Saavedra ◽  
James O Wrabl ◽  
Hesam N Motlagh ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Structural Changes ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Control Function ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Novel Strategy ◽  
Structured Proteins

Intrinsically disordered proteins (IDPs) present a functional paradox because they lack stable tertiary structure, but nonetheless play a central role in signaling, utilizing a process known as allostery. Historically, allostery in structured proteins has been interpreted in terms of propagated structural changes that are induced by effector binding. Thus, it is not clear how IDPs, lacking such well-defined structures, can allosterically affect function. Here, we show a mechanism by which an IDP can allosterically control function by simultaneously tuning transcriptional activation and repression, using a novel strategy that relies on the principle of ‘energetic frustration’. We demonstrate that human glucocorticoid receptor tunes this signaling in vivo by producing translational isoforms differing only in the length of the disordered region, which modulates the degree of frustration. We expect this frustration-based model of allostery will prove to be generally important in explaining signaling in other IDPs.

scholarly journals Highly Diverse Protein Library Based on the Ubiquitous (β/α)8Enzyme Fold Yields Well-Structured Proteins through in Vitro Folding Selection

ChemBioChem ◽  
2013 ◽  
Vol 14 (13) ◽  
pp. 1553-1563 ◽  
Author(s):  
Misha V. Golynskiy ◽  
John C. Haugner ◽  
Burckhard Seelig
Keyword(s):  
Protein Library ◽  
Structured Proteins

scholarly journals Intrinsically disordered proteins and structured proteins with intrinsically disordered regions have different functional roles in the cell

2019 ◽  
Author(s):  
Antonio Deiana ◽  
Sergio Forcelloni ◽  
Alessandro Porrello ◽  
Andrea Giansanti
Keyword(s):  
Binding Proteins ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
General Category ◽  
Large Set ◽  
Functional Roles ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Structured Proteins ◽  
Disordered Regions

AbstractMany studies about classification and the functional annotation of intrinsically disordered proteins (IDPs) are based on either the occurrence of long disordered regions or the fraction of disordered residues in the sequence. Taking into account both criteria we separate the human proteome, taken as a case study, into three variants of proteins: i) ordered proteins (ORDPs), ii) structured proteins with intrinsically disordered regions (IDPRs), and iii) intrinsically disordered proteins (IDPs). The focus of this work is on the different functional roles of IDPs and IDPRs, which up until now have been generally considered as a whole. Previous studies assigned a large set of functional roles to the general category of IDPs. We show here that IDPs and IDPRs have non-overlapping functional spectra, play different roles in human diseases, and deserve to be treated as distinct categories of proteins. IDPs enrich only a few classes, functions, and processes: nucleic acid binding proteins, chromatin binding proteins, transcription factors, and developmental processes. In contrast, IDPRs are spread over several functional protein classes and GO annotations which they partly share with ORDPs. As regards to diseases, we observe that IDPs enrich only cancer-related proteins, at variance with previous results reporting that IDPs are widespread also in cardiovascular and neurodegenerative pathologies. Overall, the operational separation of IDPRs from IDPs is relevant towards correct estimates of the occurrence of intrinsically disordered proteins in genome-wide studies and in the understanding of the functional spectra associated to different flavors of protein disorder.

scholarly journals Mass spectrometry reveals the chemistry of formaldehyde cross-linking in structured proteins

2019 ◽  
Author(s):  
Tamar Tayri-Wilk ◽  
Moriya Slavin ◽  
Joanna Zamel ◽  
Ayelet Blass ◽  
Shon Cohen ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Carbon Atom ◽  
Mass Spectrometry Data ◽  
Cross Linking ◽  
Atomic Structures ◽  
Cross Links ◽  
Structured Proteins ◽  
Structural Insights ◽  
Current Mechanism

AbstractFormaldehyde is a widely used fixative in biology and medicine. The current mechanism of formaldehyde cross-linking of proteins is the formation of a methylene bridge that incorporates one carbon atom into the link. Here, we present mass spectrometry data that largely refute this mechanism. Instead, the data reveal that cross-linking of structured proteins mainly involves a reaction that incorporates two carbon atoms into the link. Under MS/MS fragmentation, the link cleaves symmetrically to yield previously unrecognized fragments carrying a modification of one carbon atom. If these characteristics are considered, then formaldehyde cross-linking is readily applicable to the structural approach of cross-linking coupled to mass spectrometry. Using a cross-linked mixture of purified proteins, a suitable analysis identifies tens of cross-links that fit well with their atomic structures. A more elaborate in situ cross-linking of human cells in culture identified 469 intra-protein and 90 inter-protein cross-links, which also agreed with available atomic structures. Interestingly, many of these cross-links could not be mapped onto a known structure and thus provide new structural insights. For example, two cross-links involving the protein βNAC localize its binding site on the ribosome. Also of note are cross-links of actin with several auxiliary proteins for which the structure is unknown. Based on these findings we suggest a revised chemical reaction, which has relevance to the reactivity and toxicity of formaldehyde.

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