scholarly journals Biases in the Experimental Annotations of Protein Function and Their Effect on Our Understanding of Protein Function Space

2013 ◽  
Vol 9 (5) ◽  
pp. e1003063 ◽  
Author(s):  
Alexandra M. Schnoes ◽  
David C. Ream ◽  
Alexander W. Thorman ◽  
Patricia C. Babbitt ◽  
Iddo Friedberg
Keyword(s):  
Function Space ◽  
Protein Function

scholarly journals Protein function space: viewing the limits or limited by our view?

2007 ◽  
Vol 17 (3) ◽  
pp. 362-369 ◽  
Author(s):  
Jeroen Raes ◽  
Eoghan Donal Harrington ◽  
Amoolya Hardev Singh ◽  
Peer Bork
Keyword(s):  
Function Space ◽  
Protein Function

scholarly journals Darkness in the Human Gene and Protein Function Space: Widely Modest or Absent Illumination by the Life Science Literature and the Trend for Fewer Protein Function Discoveries Since 2000

PROTEOMICS ◽  
2018 ◽  
Vol 18 (21-22) ◽  
pp. 1800093 ◽  
Author(s):  
Swati Sinha ◽  
Birgit Eisenhaber ◽  
Lars Juhl Jensen ◽  
Bharata Kalbuaji ◽  
Frank Eisenhaber
Keyword(s):  
Function Space ◽  
Protein Function ◽  
Life Science ◽  
Human Gene ◽  
Science Literature

On the Use of POCS for Restoring the “Missing Wedge” in Electron Tomography

1990 ◽  
Vol 48 (1) ◽  
pp. 520-521
Author(s):  
Neng-Yu Zhang ◽  
Bruce F. McEwen ◽  
Joachim Frank
Keyword(s):  
Function Space ◽  
Convex Sets ◽  
Electron Tomography ◽  
Spinal Ganglion ◽  
Fourier Space ◽  
Missing Information ◽  
Voltage Electron ◽  
High Voltage Electron Microscope ◽  
Energy Bound ◽  
Spatial Boundedness

Reconstructions of asymmetric objects computed by electron tomography are distorted due to the absence of information, usually in an angular range from 60 to 90°, which produces a “missing wedge” in Fourier space. These distortions often interfere with the interpretation of results and thus limit biological ultrastructural information which can be obtained. We have attempted to use the Method of Projections Onto Convex Sets (POCS) for restoring the missing information. In POCS, use is made of the fact that known constraints such as positivity, spatial boundedness or an upper energy bound define convex sets in function space. Enforcement of such constraints takes place by iterating a sequence of function-space projections, starting from the original reconstruction, onto the convex sets, until a function in the intersection of all sets is found. First applications of this technique in the field of electron microscopy have been promising.To test POCS on experimental data, we have artificially reduced the range of an existing projection set of a selectively stained Golgi apparatus from ±60° to ±50°, and computed the reconstruction from the reduced set (51 projections). The specimen was prepared from a bull frog spinal ganglion as described by Lindsey and Ellisman and imaged in the high-voltage electron microscope.

Reading the phosphorylation code: binding of the 14-3-3 protein to multivalent client phosphoproteins

2020 ◽  
Vol 477 (7) ◽  
pp. 1219-1225 ◽  
Author(s):  
Nikolai N. Sluchanko
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Protein ◽  
Structural Basis ◽  
Major Protein ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Biochemical Journal ◽  
Multiple Binding ◽  
And Control

Many major protein–protein interaction networks are maintained by ‘hub’ proteins with multiple binding partners, where interactions are often facilitated by intrinsically disordered protein regions that undergo post-translational modifications, such as phosphorylation. Phosphorylation can directly affect protein function and control recognition by proteins that ‘read’ the phosphorylation code, re-wiring the interactome. The eukaryotic 14-3-3 proteins recognizing multiple phosphoproteins nicely exemplify these concepts. Although recent studies established the biochemical and structural basis for the interaction of the 14-3-3 dimers with several phosphorylated clients, understanding their assembly with partners phosphorylated at multiple sites represents a challenge. Suboptimal sequence context around the phosphorylated residue may reduce binding affinity, resulting in quantitative differences for distinct phosphorylation sites, making hierarchy and priority in their binding rather uncertain. Recently, Stevers et al. [Biochemical Journal (2017) 474: 1273–1287] undertook a remarkable attempt to untangle the mechanism of 14-3-3 dimer binding to leucine-rich repeat kinase 2 (LRRK2) that contains multiple candidate 14-3-3-binding sites and is mutated in Parkinson's disease. By using the protein-peptide binding approach, the authors systematically analyzed affinities for a set of LRRK2 phosphopeptides, alone or in combination, to a 14-3-3 protein and determined crystal structures for 14-3-3 complexes with selected phosphopeptides. This study addresses a long-standing question in the 14-3-3 biology, unearthing a range of important details that are relevant for understanding binding mechanisms of other polyvalent proteins.

The challenge of detecting modifications on proteins

2020 ◽  
Vol 64 (1) ◽  
pp. 135-153 ◽  
Author(s):  
Lauren Elizabeth Smith ◽  
Adelina Rogowska-Wrzesinska
Keyword(s):  
Mass Spectrometry ◽  
Protein Function ◽  
Chemical Properties ◽  
Lysine Acetylation ◽  
Mass Determination ◽  
Post Translational Modifications ◽  
Site Specific ◽  
The Common

Abstract Post-translational modifications (PTMs) are integral to the regulation of protein function, characterising their role in this process is vital to understanding how cells work in both healthy and diseased states. Mass spectrometry (MS) facilitates the mass determination and sequencing of peptides, and thereby also the detection of site-specific PTMs. However, numerous challenges in this field continue to persist. The diverse chemical properties, low abundance, labile nature and instability of many PTMs, in combination with the more practical issues of compatibility with MS and bioinformatics challenges, contribute to the arduous nature of their analysis. In this review, we present an overview of the established MS-based approaches for analysing PTMs and the common complications associated with their investigation, including examples of specific challenges focusing on phosphorylation, lysine acetylation and redox modifications.

Finite-order Integration Weights Can be Dangerous

2007 ◽  
Vol 7 (3) ◽  
pp. 239-254 ◽  
Author(s):  
I.H. Sloan
Keyword(s):  
Function Space ◽  
Finite Order ◽  
Small Subset ◽  
Worst Case ◽  
Integration Rule ◽  
Dimensional Lattice ◽  
3 Dimensional ◽  
Sum Of Functions ◽  
Integration Rules

Abstract Finite-order weights have been introduced in recent years to describe the often occurring situation that multivariate integrands can be approximated by a sum of functions each depending only on a small subset of the variables. The aim of this paper is to demonstrate the danger of relying on this structure when designing lattice integration rules, if the true integrand has components lying outside the assumed finiteorder function space. It does this by proving, for weights of order two, the existence of 3-dimensional lattice integration rules for which the worst case error is of order O(N¯½), where N is the number of points, yet for which there exists a smooth 3- dimensional integrand for which the integration rule does not converge.

Spatial localization of unknown proteins in the endoplasmic reticulum predicts functions

2007 ◽  
Vol 30 (4) ◽  
pp. 84
Author(s):  
Michael D. Jain ◽  
Hisao Nagaya ◽  
Annalyn Gilchrist ◽  
Miroslaw Cygler ◽  
John J.M. Bergeron
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Protein Synthesis ◽  
Protein Function ◽  
Protein Translocation ◽  
Spatial Localization ◽  
Predict Protein Function ◽  
Insight Into ◽  
Soluble Fractions ◽  
Er Membrane

Protein synthesis, folding and degradation functions are spatially segregated in the endoplasmic reticulum (ER) with respect to the membrane and the ribosome (rough and smooth ER). Interrogation of a proteomics resource characterizing rough and smooth ER membranes subfractionated into cytosolic, membrane, and soluble fractions gives a spatial map of known proteins involved in ER function. The spatial localization of 224 identified unknown proteins in the ER is predicted to give insight into their function. Here we provide evidence that the proteomics resource accurately predicts the function of new proteins involved in protein synthesis (nudilin), protein translocation across the ER membrane (nicalin), co-translational protein folding (stexin), and distal protein folding in the lumen of the ER (erlin-1, TMX2). Proteomics provides the spatial localization of proteins and can be used to accurately predict protein function.

Coaction of Electrostatic and Hydrophobic Interactions: Dynamic Constraints on Disordered TrkA Juxtamembrane Domain

2019 ◽  
Author(s):  
Zichen Wang ◽  
Huaxun Fan ◽  
Xiao Hu ◽  
John Khamo ◽  
Jiajie Diao ◽  
...  
Keyword(s):  
Single Molecule ◽  
Protein Function ◽  
Hydrophobic Interactions ◽  
Transmembrane Helix ◽  
Point Mutations ◽  
Salt Bridge ◽  
Receptor Activation ◽  
Membrane Dynamics ◽  
Juxtamembrane Domain ◽  
Joint Work

<p>The receptor tyrosine kinase family transmits signals into cell via a single transmembrane helix and a flexible juxtamembrane domain (JMD). Membrane dynamics makes it challenging to study the structural mechanism of receptor activation experimentally. In this study, we employ all-atom molecular dynamics with Highly Mobile Membrane-Mimetic to capture membrane interactions with the JMD of tropomyosin receptor kinase A (TrkA). We find that PIP<sub>2 </sub>lipids engage in lasting binding to multiple basic residues and compete with salt bridge within the peptide. We discover three residues insertion into the membrane, and perturb it through computationally designed point mutations. Single-molecule experiments indicate the contribution from hydrophobic insertion is comparable to electrostatic binding, and in-cell experiments show that enhanced TrkA-JMD insertion promotes receptor ubiquitination. Our joint work points to a scenario where basic and hydrophobic residues on disordered domains interact with lipid headgroups and tails, respectively, to restrain flexibility and potentially modulate protein function.</p>

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