Design principles involving protein disorder facilitate specific substrate selection and degradation by the ubiquitin-proteasome system

The ubiquitin-proteasome system (UPS) regulates diverse cellular pathways by the timely removal (or processing) of proteins. Here we review the role of structural disorder and conformational flexibility in the different aspects of degradation. First, we discuss post-translational modifications within disordered regions that regulate E3 ligase localization, conformation, and enzymatic activity, and also the role of flexible linkers in mediating ubiquitin transfer and reaction processivity. Next we review well studied substrates and discuss that substrate elements (degrons) recognized by E3 ligases are highly disordered: short linear motifs recognized by many E3s constitute an important class of degrons, and these are almost always present in disordered regions. Substrate lysines targeted for ubiquitination are also often located in neighboring regions of the E3 docking motifs and are therefore part of the disordered segment. Finally, biochemical experiments and predictions show that initiation of degradation at the 26S proteasome requires a partially unfolded region to facilitate substrate entry into the proteasomal core. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc

Polariton Emission Characteristics of a Modulation-Doped Multiquantum-Well Microcavity Diode

The role of polariton-electron scattering on the performance characteristics of an electrically injected GaAs-based quantum well microcavity diode in the strong coupling regime has been investigated. An electron gas is introduced in the quantum wells by modulation doping with silicon dopants. It is observed that polariton-electron scattering suppresses the relaxation bottleneck in the lower polariton branch. However, it is not adequate to produce a degenerate coherent condensate at k|| ~ 0 and coherent emission.Comment: 14 pages, 4 figures, submitted to Applied Physics Letter

Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway

The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. © 2013 Bhowmick et al

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Copia digital. Madrid : Ministerio de Cultura. Subdirección General de Coordinación Bibliotecaria, 200

Supplementary Table 3.11.xlsx

<p>These are supporting information related to PhD thesis.</p> <p>All rights reserved</p> <p>© 2015 Pallab Bhowmick</p> <p>Apart from any fair dealing for the purposes of research, private study, criticism or review, this publication may not be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, scanning, or otherwise), without prior written permission of the author.</p

Supplementary Table 2.3.xls

<p>These are supporting information related to PhD thesis.</p> <p>All rights reserved</p> <p>© 2015 Pallab Bhowmick</p> <p>Apart from any fair dealing for the purposes of research, private study, criticism or review, this publication may not be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, scanning, or otherwise), without prior written permission of the author.</p

The role of structural disorder in the degradation signal in the ubiquitin-proteasome pathway

<p>These are supporting information related to PhD thesis.</p> <p>All rights reserved</p> <p>© 2015 Pallab Bhowmick</p> <p>Apart from any fair dealing for the purposes of research, private study, criticism or review, this publication may not be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, scanning, or otherwise), without prior written permission of the author.</p

The role of structural disorder in the degradation signal in the ubiquitin-proteasome pathway

<p>These are supporting information related to PhD thesis.</p> <p>All rights reserved</p> <p>© 2015 Pallab Bhowmick</p> <p>Apart from any fair dealing for the purposes of research, private study, criticism or review, this publication may not be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, scanning, or otherwise), without prior written permission of the author.</p

Supplementary Table 3.5.xlsx

<p>These are supporting information related to PhD thesis.</p> <p>All rights reserved</p> <p>© 2015 Pallab Bhowmick</p> <p>Apart from any fair dealing for the purposes of research, private study, criticism or review, this publication may not be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, scanning, or otherwise), without prior written permission of the author.</p

Supplementary Table 3.10.xlsx

<p>These are supporting information related to PhD thesis.</p> <p>All rights reserved</p> <p>© 2015 Pallab Bhowmick</p> <p>Apart from any fair dealing for the purposes of research, private study, criticism or review, this publication may not be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, scanning, or otherwise), without prior written permission of the author.</p