Biology subjects

Arif, U.

Publications and source records attributed to Arif, U..

3 recordsLinked to original sources

bioRxiv2026

AlphaFold3 predictions of novel GLI-SUFU interfaces identify binding-defective SUFU missense variants from medulloblastoma and Gorlin Syndrome patients

The tumor suppressor SUFU is a key negative regulator of oncogenic GLI transcription factors. SUFU mutations predispose to medulloblastoma and can cause Gorlin and Joubert syndromes. Limited structural information is available on the GLI-SUFU complex, contributing to the fact that the vast majority of SUFU missense variants sequenced from affected patients are of unknown clinical significance. Using AlphaFold3 and complementary computational analysis, we predicted structures of the three human GLI-SUFU complexes and the orthologous Drosophila Ci-Sufu complex, revealing previously unrecognized contact interfaces. By site-directed mutagenesis and GLI-SUFU binding assays, we validated the importance of key interface residues, many of which are mutated in familial medulloblastoma and Gorlin syndrome. These findings provide new structure-function insights into a signaling complex mutated in cancer and rare congenital diseases, and offer an expanded framework for interpreting clinically observed SUFU variants and mechanisms that tune SUFU repression. TeaserAI-powered modeling plus experimental validation reveal new GLI-SUFU interfaces linked to cancer and congenital mutations.

biochemistry↗

bioRxiv2020

GEMC1-MCIDAS transcriptional program regulates multiciliogenesis in the choroid plexus and acts as a barrier to tumorigenesis

Multiciliated cells (MCCs) in the brain include the ependymal cells and choroid plexus (CP) epithelial cells. The CP secretes cerebrospinal fluid that circulates within the ventricular system, driven by ependymal cilia movement. However, the mechanisms and functional significance of multiciliogenesis in the CP remain unknown. Deregulated oncogenic signals cause CP carcinoma (CPC), a rare but aggressive pediatric brain cancer. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. NOTCH-driven CP tumors were monociliated, whereas disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of GEMC1 and MCIDAS, early regulators of multiciliogenesis. Consistently, GEMC1-MCIDAS function is essential for multiciliation in the CP, and is critical for correcting multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to the GEMC1 program are commonly observed in human CPCs characterized by solitary cilia. Consistently, CPC driven by deletion of Trp53 and Rb1 in mice exhibits a cilia deficit consequent to loss of Gemc1-Mcidas expression. Taken together, these findings reveal a GEMC1-MCIDAS multiciliation program in the CP critical for inhibiting tumorigenesis, and it may have therapeutic implications for the treatment of CPC.

cancer biology↗

bioRxiv2017

Ultrafast glutamate sensors resolve synaptic short-term plasticity

Glutamatergic synapses display a rich repertoire of plasticity mechanisms on many different time scales, involving dynamic changes in the efficacy of transmitter release as well as changes in the number and function of postsynaptic glutamate receptors. The genetically encoded glutamate sensor iGluSnFR enables visualization of glutamate release from presynaptic terminals at frequencies up to [~]10 Hz. However, to resolve glutamate dynamics during high frequency bursts, faster indicators are required. Here we report the development of fast (iGluf) and ultrafast (iGluu) variants with comparable brightness, but increased Kd for glutamate (137 M and 600 M, respectively). Compared to iGluSnFR, iGluu has a 6-fold faster dissociation rate in vitro and 5-fold faster kinetics in synapses. Fitting a three-state model to kinetic data, we identify the large conformational change after glutamate binding as the rate-limiting step. In rat hippocampal slice culture stimulated at 100 Hz, we find that iGluu is sufficiently fast to resolve individual glutamate release events, revealing that glutamate is rapidly cleared from the synaptic cleft. Depression of iGluu responses during 100 Hz trains correlates with depression of postsynaptic EPSPs, indicating that depression during high frequency stimulation is purely presynaptic in origin. At individual boutons, the recovery from depression could be predicted from the amount of glutamate released on the second pulse (paired pulse facilitation/depression), demonstrating differential frequency-dependent filtering of spike trains at Schaffer collateral boutons.\n\nSignificance StatementExcitatory synapses convert presynaptic action potentials into chemical signals that are sensed by postsynaptic glutamate receptors. To eavesdrop on synaptic transmission, genetically encoded fluorescent sensors for glutamate have been developed. However, even the best available sensors lag behind the very fast glutamate dynamics in the synaptic cleft. Here we report the development of an ultrafast genetically encoded glutamate sensor, iGluu, which allowed us to image glutamate clearance and synaptic depression during 100 Hz spike trains. We found that only boutons showing paired-pulse facilitation were able to rapidly recover from depression. Thus, presynaptic boutons act as frequency-specific filters to transmit select features of the spike train to specific postsynaptic cells.

neuroscience↗