Biology subjects

Christian, B.

Publications and source records attributed to Christian, B..

3 recordsLinked to original sources

bioRxiv2025

The impact of N-terminal dimerization on formin homology 1 (FH1) domain polymer dynamics and actin assembly

Many proteins contain intrinsically disordered regions (IDRs) that lack stable 3-dimensional structure. IDR behavior is poorly understood, leading to challenges for biochemical and computational analysis of IDR-containing proteins. Formins are a diverse set of homodimers containing an IDR -- the FH1 domain -- that facilitates polymerization of the cytoskeletal protein actin by increasing the local concentration of actin monomers at the actin assembly site. A commonly accepted model of formin-based actin polymerization involves a capture-and-deliver process: one or more binding sites (proline-rich motifs, PRMs) "capture" actin monomers and then "deliver" actin to the actin assembly site. There is evidence that formin FH1 domains are dimerized on both ends, but much research has been performed with formin constructs lacking the N-terminal dimerization site. Here, we ask: What happens when N-terminal dimerization is added to the standard model of formin-mediated actin assembly? We extend the kinetic model of FH1-mediated actin polymerization by incorporating a coarse-grain polymer model of FH1 domain dynamics, modeling the FH1 domain as a freely-jointed chain. We find that N-terminal dimerization can impact polymerization rates by modifying binding site accessibility and/or local concentration of binding sites (PRMs) at the actin assembly site (FH2 domain). Which effect dominates depends on kinetic parameters and formin properties such as FH1 domain length and binding site location. Additionally, we demonstrate that our model can be fit to experimental data and used to make predictions for the effects of N-terminal dimerization on a variety of formin family members. SignificanceIntrinsically disordered regions (IDRs) are common protein components that lack stable 3D structures and are thus difficult to study. Here, we develop a polymer-physics based computational model of the formin FH1 domain, an IDR involved in building the cells cytoskeleton. Some disease-associated mutations of formins occur in a region that is suspected to induce dimerization, forcing the FH1 domains to form a loop. Little is known about the loops prevalence, location, or impact on cytoskeletal assembly. Using simple polymer physics, we demonstrate that this dimerization can alter FH1 domain polymer dynamics and thus impact cytoskeletal assembly. These results not only highlight an important aspect of FH1-mediated cytoskeletal assembly, but also provide a framework for modeling IDRs.

biophysics↗

bioRxiv2023

Blocking Orai1 constitutive activity inhibits B-cell cancer migration and synergistically acts with drugs to reduce B-CLL cell survival

Orai1 channel capacity to control store-operated Ca2+ entry (SOCE) and B-cell functions is poorly understood and more specifically in B-cell cancers, including human lymphoma and leukemia. As compared to normal B-cells, Orai1 is overexpressed in B-chronic lymphocytic leukemia (B-CLL) and contributes in resting B-CLL to mediate an elevated basal Ca2+ level through a constitutive Ca2+ entry, and in BCR-activated B-cell to regulate the Ca2+ signaling response. Such observations were confirmed in human B-cell lymphoma and leukemia lines, including RAMOS, JOK-1, MEC-1 and JVM-3 cells. Next, the use of pharmacological Orai1 inhibitors (GSK-7975A and Synta66) blocks constitutive Ca2+ entry and in turn affects B-cell cancer (primary and cell lines) survival and migration, controls cell cycle, and induces apoptosis through a mitochondrial and caspase-3 independent pathway. Finally, the added value of Orai1 inhibitors in combination with B-CLL drugs (ibrutinib, idelalisib, rituximab, and venetoclax) on B-CLL survival was tested, showing an additive/synergistic effect including in the B-cell cancer lines. To conclude, this study highlights the pathophysiological role of the Ca2+ channel Orai1 in B-cell cancers, and pave the way for the use of ORAI1 modulators as a plausible therapeutic strategy.

cancer biology↗

bioRxiv2020

Proper names from story recall are associated with beta-amyloid in cognitively unimpaired adults at risk for Alzheimer's disease

Due to advances in the early detection of Alzheimers disease (AD) biomarkers including beta-amyloid (A{beta}), neuropsychological measures that are sensitive to concurrent, subtle changes in cognition are critically needed. Story recall tasks have shown sensitivity to early memory declines in persons with Mild Cognitive Impairment and early stage dementia, as well as in persons with autosomal dominantly inherited AD up to 10 years prior to a dementia diagnosis. However, the evidence is inconclusive regarding relationships between evidence of A{beta} and story recall measures. Because story recall tasks require the encoding and delayed retrieval of several lexical-semantic categories, such as proper names, verbs, and numerical expressions, and because lexical categories have been shown to be differentially impaired in persons with MCI, we focused on item-level analyses of lexical-semantic retrieval from a quintessential story recall task, Logical Memory from the Wechsler Memory Scale. Our objective was to investigate whether delayed recall of lexical categories (proper names, verbs and/or numerical expressions), as well as the traditional total score measure, was associated with "preclinical AD," or cognitively unimpaired adults with positive A{beta} deposition on positron emission tomography (PET) neuroimaging using Pittsburgh Compound B. We developed an item-level scoring system, in which we parsed items into lexical categories and examined the immediate and delayed recall of these lexical categories from 217 cognitively unimpaired participants from the Wisconsin Registry for Alzheimers Prevention. We performed binary logistic regression models with story recall score as predictor and A{beta} status (positive/negative) as the outcome. Using baseline Logical Memory data, proper names from delayed story recall were significantly associated with A{beta} status, such that participants who recalled more proper names were less likely to be classified as PiB(+) (odds ratio = .58, p=.01). None of the other story recall variables, including total score, were associated with PiB status. Secondary analyses determined that immediate recall of proper names was not significantly associated with A{beta}, suggesting a retrieval deficit rather than that of encoding. The present findings suggest that lexical semantic retrieval measures from existing story recall tasks may be sensitive to A{beta} deposition, and may provide added utility to a widely-used, long-standing neuropsychological test for early detection of cognitive decline on the AD continuum.

neuroscience↗