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Biology subjects

ElSheikh, A.

Publications and source records attributed to ElSheikh, A..

3 recordsLinked to original sources

Virtual Cells Need Context, Not Just Scale

The intersection of AI and biology has entered a phase of explosive growth, driven by the ambition to build "Virtual Cells" or computational models capable of predicting cellular responses to any perturbation. Following the success of structural biology (e.g., AlphaFold) and large language models, the field has converged on training massive, high-capacity models on large-scale single-cell data. This position paper argues that scaling model capacity is insufficient to solve the Virtual Cell problem because the primary failure mode is a lack of adequate coverage over diverse biological contexts, not insufficient model expressivity. We support this claim by reviewing recent studies showing that simple baselines perform on par with sophisticated architectures within a given biological context, and current models fail to consistently generalize across contexts. We connect this finding to the causal inference literature on transportability and contrast it with domains where scaling has succeeded. We substantiate our argument through analysis of a state-of-the-art model on a 22-million-cell immunology dataset. We conclude that the community faces a causal transport problem that cannot be solved by accumulating more data from the same distributions. Instead, we argue that contextual diversity and causal representation learning deserve increased emphasis, complementing ongoing scaling of model capacity and data volume.

genomics↗

Identification and Rescue of Congenital Hyperinsulinism-Associated ABCC8 Mutations that Impair KATP Channel Trafficking

ATP-sensitive potassium (KATP) channels composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) couple glucose metabolism with insulin secretion in pancreatic {beta}-cells and are vital to glucose homeostasis. Loss-of-function mutations in SUR1 and Kir6.2, encoded by ABCC8 and KCNJ11, respectively are the commonest causes of severe persistent hypoglycemia in infants and children seen in the rare disease congenital hyperinsulinism (HI). The N-terminal transmembrane domain, TMD0, and the linker immediately C-terminal to TMD0, L0, of SUR1 (TMD0/L0) forms direct contact with Kir6.2 in KATP channels. Mutations in SUR1-TMD0 often impair KATP channel trafficking to the plasma membrane, causing severe disease unresponsive to treatment by the KATP activator diazoxide; however, surface expression and function of many such mutant channels can be rescued by reversible KATP inhibitor pharmacochaperones. Here, we identified seven new SUR1 missense mutations in TMD0/L0 from HI patients unresponsive to diazoxide and investigated their effects on KATP channel expression, function, and response to pharmacochaperones. All seven mutations, N32K, Y124F, P133R, W143R, L171P, G228D, and Y230C, reduced channel function in Rb+ efflux assays. Further characterization by immunoblotting, immunostaining and electrophysiology revealed that Y124F primarily causes defective channel gating, while the others impair channel trafficking to different extents. The trafficking mutations showed varied response to surface expression and function rescue by the reversible KATP inhibitor pharmacochaperones, tolbutamide and Aekatperone. The study underscores the critical role of SUR1-TMD0/L0 in KATP expression and gating. It further highlights the importance of detailed biochemical and functional studies of mutant channels in understanding their pathogenic roles and response to potential pharmacological therapies.

biochemistry↗

Structure of an open KATP channel reveals tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface

ATP-sensitive potassium (KATP) channels, composed of four pore-lining Kir6.2 subunits and four regulatory sulfonylurea receptor 1 (SUR1) subunits, control insulin secretion in pancreatic {beta}-cells. KATP channel opening is stimulated by PIP2 and inhibited by ATP. Mutations that increase channel opening by PIP2 reduce ATP inhibition and cause neonatal diabetes. Although considerable evidence has implicated a role for PIP2 in KATP channel function, previously solved open-channel structures have lacked bound PIP2, and mechanisms by which PIP2 regulates KATP channels remain unresolved. Here, we report cryoEM structure of a KATP channel harboring the neonatal diabetes mutation Kir6.2-Q52R, bound to natural C18:0/C20:4 long-chain PI(4,5)P2 in open conformation. The structure reveals two adjacent PIP2 molecules between SUR1 and Kir6.2. The first PIP2 binding site is conserved among PIP2-gated Kir channels. The second site forms uniquely in KATP at the interface of Kir6.2 and SUR1. Functional studies demonstrate both binding sites determine channel activity. Kir6.2 pore opening is associated with a twist of the Kir6.2 cytoplasmic domain and a rotation of the N-terminal transmembrane domain of SUR1, which widens the inhibitory ATP binding pocket to disfavor ATP binding. The open conformation is particularly stabilized by the Kir6.2-Q52R residue through cation-{pi} bonding with SUR1 - W51. Together, these results uncover the cooperation between SUR1 and Kir6.2 in PIP2 binding and gating, explain the antagonistic regulation of KATP channels by PIP2 and ATP, and provide the mechanism by which Kir6.2-Q52R stabilizes an open channel to cause neonatal diabetes.

biochemistry↗