Biology subjects

Pedersen, H.

Publications and source records attributed to Pedersen, H..

6 recordsLinked to original sources

bioRxiv2024

Cryo-EM analysis of complement C3 reveals a reversible major opening of the macroglobulin ring

The C3 protein is the central molecule within the complement system and undergoes pattern-recognition-dependent proteolytic activation to C3b in the presence of pathogens and damage-associated patterns. Spontaneous pattern-independent activation of C3 occurs via hydrolysis, resulting in C3(H2O). However, the structural details of C3 hydrolysis remain elusive. Here, we show that the conformation of the C3(H2O) analog, C3MA, in which the C3 thioester is broken by aminolysis is indistinguishable from C3b except for the 77-residue anaphylatoxin (ANA) domain. In contrast, the reaction intermediate C3* formed during C3 adopts a dynamic conformation dramatically different from both C3 and C3MA/C3b. In C3*, unlocking of the macroglobulin (MG) 3 domain creates a large opening in the MG-ring through which the ANA domain translocates. In support of this mechanism, C3MA formation is inhibited by an MG3/MG4-interface-specific nanobody and prevented by linking the ANA domain to the C3 {beta}-chain. Our study reveals an unexpected dynamic behavior of C3 where an exceptional conformational change allows the translocation of an entire domain through a large dynamic opening. These results form the basis for elucidation of the in vivo contribution of C3 hydrolysis to complement activation and offer a rational approach for modulation of C3(H2O) with the potential for preventing complement activation caused by intravascular hemolysis and surface contacts.

biochemistry↗

bioRxiv2023

Retracing Human Genetic Histories and Natural Selection Using Precise Local Ancestry Inference

In an increasingly diverse world, including admixed individuals in genomic studies is imperative for equity and portability. A crucial first step is precise local ancestry inference (LAI). We have developed Orchestra, a LAI model with unprecedented accuracy, and trained on over 10,000 single-origin individuals from 35 worldwide populations. We employed Orchestra to delve into genetic relationships and demographic histories, with a focus on Latin Americans, a prime example of admixture, and the Ashkenazi Jewish, whose origins have long been debated. Finally, Orchestra enabled us to map signatures of selection, notably identifying trace Scandinavian ancestry in British samples and unveiling an immune-rich region linked to respiratory infections. Our work advances the field of LAI and holds promise for improvements in future applications for admixed populations. One-Sentence SummaryOrchestra unveils Latino and Ashkenazi ancestral roots and a candidate Viking locus under selection in the British population

genomics↗

bioRxiv2021

EZTraits: a Programmable Tool to Evaluate Multi-site Deterministic Traits

The vast majority of human traits, including many disease phenotypes, are affected by alleles at numerous genomic loci. With a continually increasing set of variants with published clinical disease or biomarker associations, an easy-to-use tool for non-programmers to rapidly screen VCF files for risk alleles is needed. We have developed EZTraits as a tool to quickly evaluate genotype data (e.g., from microarrays) against a set of rules defined by the user. These rules can be defined directly in the scripting language Lua, for genotype calls using variant ID (RS number) or chromosomal position. Alternatively, EZTraits can parse simple and intuitive text including concepts like any or all. Thus, EZTraits is designed to support rapid genetic analysis and hypothesis-testing by researchers, regardless of programming experience or technical background. The software is implemented in C++ and compiles and runs on Linux and MacOS. The source code is available under the MIT license from https://github.com/selfdecode/rd-eztraits Contact: manfred@selfdecode.com

bioinformatics↗

bioRxiv2021

Structure of the integrin receptor M2 headpiece in complex with a function-modulating nanobody

The integrin receptor M{beta}2 mediates phagocytosis of complement-opsonized objects, adhesion to the extracellular matrix and trans-endothelial migration of leukocytes. Here we present the first atomic structure of the human M{beta}2 headpiece fragment in complex with the nanobody hCD11bNb1 determined at a resolution of 3.2 [A]. The receptor headpiece adopts the closed conformation expected to have low ligand affinity. The crystal structure advocates that in the R77H M variant associated with systemic lupus erythematosus, the modified allosteric coupling between ligand coupling and integrin outside-inside signalling is due to subtle conformational effects transmitted over 40 [A]. The nanobody binds to the I domain of the M subunit in an Mg2+ independent manner with low nanomolar affinity. Biochemical and biophysical experiments with purified proteins argue that the nanobody acts as a competitive inhibitor through steric hindrance exerted on the thioester domain of iC3b attempting to bind the M subunit. Surprisingly, the nanobody stimulates the interaction of cell-bound M{beta}2 with iC3b suggesting that it represents a novel high-affinity proteinaceous M{beta}2 specific agonist. We propose a model based on the conformational spectrum of the receptor to reconcile these conflicting observations regarding the functional consequences of hCD11bNb1 binding to M{beta}2. Furthermore, our data suggest that the iC3b-M{beta}2 complex may be more dynamic than predicted from the crystal structure of the core complex.

immunology↗

bioRxiv2020

Impacts of predator-mediated interactions along a climatic gradient on the population dynamics of an alpine bird

According to classic theory, species population dynamics and distributions are less influenced by species interactions under harsh climatic conditions compared to under more benign climatic conditions. In alpine and boreal ecosystems in Fennoscandia, the cyclic dynamics of rodents strongly affect many other species, including ground-nesting birds such as ptarmigan. According to the alternative prey hypothesis (APH), the densities of ground-nesting birds and rodents are positively associated due to predator-prey dynamics and prey-switching. However, it remains unclear how the strength of these predator-mediated interactions change along a climatic harshness gradient in comparison with the effects of climatic variation. We built a hierarchical Bayesian model to estimate the sensitivity of ptarmigan populations to interannual variation in climate and rodent occurrence across Norway during 2007-2017. Ptarmigan abundance was positively linked with rodent occurrence, consistent with the APH. Moreover, we found that rodent dynamics had stronger effects on ptarmigan in colder regions. Our study highlights how species interactions play an important role for the population dynamics of species at higher latitudes and suggests that they can become even more important in the most climatically harsh regions.

ecology↗

bioRxiv2019

Beyond Conventional Models: Recreating the Initiation, Evolution, and Genome of GBM

BackgroundImagining ways to prevent or treat glioblastoma (GBM) have been hindered by a lack of understanding of its pathogenesis. Although PDGF-AA overexpression may be an early event, critical details of the core biology are lacking. Existing PDGF-driven models replicate its microscopic appearance but not the genomic architecture characteristic of the human disease. Here we report a new model of GBM that overcomes this barrier to authenticity. MethodsUsing a method developed to study neural stem cells, we investigated the effects of PDGF-AA on subventricular zone (SVZ) cells, the putative cell of origin of GBM. We micro-dissected SVZ tissue from p53-null and wild-type adult mice, established primary cultures in media supplemented with PDGF-AA, and assessed cell viability, proliferation, genome stability, and tumour forming potential. ResultsCounterintuitive to its canonical role as a growth factor, we observed immediate and massive death of SVZ cells in PDGF-AA. Wild-type cells did not survive in PDGF-AA. However, a small fraction of null cells evaded apoptosis, displayed attenuated proliferation, gradually accumulated whole chromosome gains and losses, and, signalled by sudden rapid proliferation and growth factor independence, became tumorigenic in immune-competent syngeneic mice. Transformed cells had an OPC-like profile, were resistant to PDGFR- inhibition, and harboured highly abnormal karyotypes similar to those seen in human GBMs. ConclusionThis model associates genome instability in SVZ cells with chronic exposure to PDGF-AA; it is the first model to replicate the genomic landscape of GBM and first in which the earliest phases of GBM can be directly observed. IMPORTANCE OF STUDYWe have developed a mouse model in which the initiation, evolution and genomic landscape of GBM can be thoroughly studied thus paving the way for ideas about how this deadly brain cancer might be prevented, interrupted at an occult stage, or treated with very different therapies.

cancer biology↗