Biology subjects

Puig, E.

Publications and source records attributed to Puig, E..

3 recordsLinked to original sources

bioRxiv2020

Somatostatin, an In Vivo Binder to Aβ Oligomers, Binds to βPFOAβ(1-42) Tetramer

Somatostatin (SST14) is strongly related to Alzheimers disease (AD), as its levels decline during aging, it regulates the proteolytic degradation of the amyloid beta peptide (A{beta}), and it binds to A{beta} oligomers in vivo. Recently, the 3D structure of a membrane-associated {beta}-sheet pore forming tetramer ({beta}PFOA{beta}(1-42) tetramer) has been reported. Here we show that SST14 binds selectively to the {beta}PFOA{beta}(1-42) tetramer without binding to monomeric A{beta}(1-42). Specific NMR chemical shift perturbations, observed during titration of SST14, define a binding site in the {beta}PFOA{beta}(1-42) tetramer and are in agreement with a 2:1 stoichiometry determined by both native MS and ITC. These results enabled us to perform driven docking and model the binding mode for the interaction. The present study provides additional evidence on the relation between SST14 and the amyloid cascade, as well as positions the {beta}PFOA{beta}(1-42) tetramer as a relevant aggregation form of A{beta} and as a potential target for AD.

biophysics↗

bioRxiv2019

Structure-based design of a Cortistatin analog with improved immunoregulatory activity against inflammatory bowel disease (IBD)

Ulcerative colitis and Crohns disease are inflammatory bowel diseases (IBD) that lead to chronic inflammations of the gastrointestinal tract due to an abnormal response of the immune system. Finding new effective drugs to tackle IBD represents a major therapeutic concern since IBD incidence and prevalence is increasing worldwide. Recent studies positioned Cortistatin (CST) as a candidate for IBD treatment due to its anti-inflammatory and immunomodulatory activity. Here, we studied the structural properties of CST using NMR and synthesized and characterized new analogs displaying enriched populations of some native conformations. One of them, Analog 5, preserved the activity against IBD with an increased half-life in serum, overcoming the native hormone limitation and opening the door for the use of CST analogs as therapeutic agents. This work represents a new approach to the rational design of molecules to treat IBD and a possibility for patients that fail to respond to other therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/839787v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@b84405org.highwire.dtl.DTLVardef@179d0bdorg.highwire.dtl.DTLVardef@775736org.highwire.dtl.DTLVardef@fea7cd_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2019

Aβ(1-42) tetramer and octamer structures reveal edge pores as a mechanism for membrane damage

The formation of amyloid-beta (A{beta}) oligomer pores in the membrane of neurons has been proposed as the means to explain neurotoxicity in Alzheimers disease (AD). It is therefore critical to characterize A{beta} oligomer samples in membrane-mimicking environments. Here we present the first three-dimensional structure of an A{beta} oligomer formed in dodecyl phosphocholine (DPC) micelles, namely an A{beta}(1-42) tetramer. It comprises a {beta}-sheet core made of six {beta}-strands, connected by only two {beta}-turns. The two faces of the {beta}-sheet core are hydrophobic and surrounded by the membrane-mimicking environment. In contrast, the edges of the core are hydrophilic and are solvent-exposed. By increasing the concentration of A{beta}(1-42), we prepared a sample enriched in A{beta}(1-42) octamers, formed by two A{beta}(1-42) tetramers facing each other forming a {beta}-sandwich structure. Notably, samples enriched in A{beta}(1-42) tetramers and octamers are both active in lipid bilayers and exhibit the same types of pore-like behaviour, but they show different occurrence rates. Remarkably, molecular dynamics simulations showed a new mechanism of membrane disruption in which water and ion permeation occurred through lipid-stabilized pores mediated by the hydrophilic residues located on the core {beta}-sheets edges of the A{beta}(1-42) tetramers and octamers.

biophysics↗