Constraints and consequences of the emergence of amino acid repeats in eukaryotic proteins

Proteins with amino acid homorepeats have the potential to be detrimental to cells and are often associated with human diseases.
Why, then, are homorepeats prevalent in eukaryotic proteomes? In yeast, homorepeats are enriched in proteins that are essential
and pleiotropic and that buffer environmental insults. The presence of homorepeats increases the functional versatility of
proteins by mediating protein interactions and facilitating spatial organization in a repeat-dependent manner. During evolution,
homorepeats are preferentially retained in proteins with stringent proteostasis, which might minimize repeat-associated
detrimental effects such as unregulated phase separation and protein aggregation. Their presence facilitates rapid protein
divergence through accumulation of amino acid substitutions, which often affect linear motifs and post-translational-modification
sites. These substitutions may result in rewiring protein interaction and signaling networks. Thus, homorepeats are distinct
modules that are often retained in stringently regulated proteins. Their presence facilitates rapid exploration of the genotype–
phenotype landscape of a population, thereby contributing to adaptation and fitness.

The paper by Chavali et al can be found here.

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Selectivity determinants of GPCR–G-protein binding

The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.

The paper by Flock et al can be found here. More information can be found here.

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Intrinsically Disordered Proteins Adaptively Reorganize Cellular Matter During Stress

Intrinsically disordered proteins (IDPs) can protect cells from diverse stresses by forming higher order assemblies such as reversible aggregates or granules. Recently, Boothby et al. show that IDPs protect tardigrades against desiccation by forming a glass-like amorphous matrix, highlighting that material properties of disordered proteins can confer adaptation during stress.

The paper by Chavali et al can be found here.

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Simultaneous quantification of protein order and disorder

Nuclear magnetic resonance spectroscopy is transforming our views of proteins by revealing how their structures and dynamics are closely intertwined to underlie their functions and interactions. Compelling representations of proteins as statistical ensembles are uncovering the presence and biological relevance of conformationally heterogeneous states, thus gradually making it possible to go beyond the dichotomy between order and disorder through more quantitative descriptions that span the continuum between them.

The paper by Sormanni et al can be found here.

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The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease.

In the 1960s, Christian Anfinsen postulated that the unique three-dimensional structure of a protein is determined by its amino acid sequence. This work laid the foundation for the sequence-structure-function paradigm, which states that the sequence of a protein determines its structure, and structure determines function. However, a class of polypeptide segments called intrinsically disordered regions does not conform to this postulate. In this review, I will first describe established and emerging ideas about how disordered regions contribute to protein function. I will then discuss molecular principles by which regulatory mechanisms, such as alternative splicing and asymmetric localization of transcripts that encode disordered regions, can increase the functional versatility of proteins. Finally, I will discuss how disordered regions contribute to human disease and the emergence of cellular complexity during organismal evolution.

The review by M. Madan Babu can be found here.

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Welcome to our sabbatical visitors!

Prof. Arthur M. Lesk from Pennsylvania State University has been visiting our group since last August, he will be here until the end of Summer. Dr Daniela Rhodes from Nanyang Technological University in Singapore visited us last month. Finally, we have Dr Richard Rottger from Denmark who joined our group as a sabbatical visitor last month. He will be with us for a couple of months.

Lesk_Arthur Daniela_Rhodes


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Francis Crick Prize Lecture 2016 by M. Madan Babu

Madan will be giving his Francis Crick Prize Lecture 2016: “Unstructured proteins: cellular complexity and human diseases” in the Royal Society, London on 7th December 2016 at 18.30! Details of the event can be found here:

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Welcome to Emily Bagge and Alex Hauser!

Welcome to Alex and Emily who will be joining us for their projects for the next couple of months.

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Welcome to Alex Gunnarsson!

Welcome to Alex who has just started his Phd in our group.

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Welcome to Dr Pavithra Lakshminarasimhan!

Welcome to Pavi who has started as a postdoc in our group.

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