Biology subjects

de Waal, M.

Publications and source records attributed to de Waal, M..

3 recordsLinked to original sources

bioRxiv2025

AI.zymes - A modular platform for evolutionary enzyme design

The ability to create new-to-nature enzymes would substantially advance bioengineering, medicine, and the chemical industry. Despite recent breakthroughs in protein design and structure prediction, designing biocatalysts with activities rivaling those of natural enzymes remains challenging. Here, we present AI.zymes, a modular platform integrating cutting-edge protein engineering algorithms within an evolutionary framework. By combining programs such as Rosetta, ESMFold, ProteinMPNN, and FieldTools in iterative rounds of design and selection, AI.zymes optimizes a broad range of catalytically relevant properties, such as transition state affinity and protein stability. Notably, AI.zymes can also improve properties that are not targeted by the employed design algorithms. For instance, AI.zymes enhanced electrostatic catalysis by iteratively selecting variants with stronger catalytic electric fields. AI.zymes was benchmarked by improving the promiscuous Kemp eliminase activity of ketosteroid isomerase, yielding a 7.7-fold increase in activity after zero-shot experimental validation of only 7 variants. Due to its modularity, AI.zymes can readily incorporate emerging design algorithms, paving the way for a unifying framework for enzyme design. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/633707v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@f2ac2eorg.highwire.dtl.DTLVardef@61b2aorg.highwire.dtl.DTLVardef@e176edorg.highwire.dtl.DTLVardef@46d692_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2023

Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity of SORL1 variants in Alzheimer's disease

SORL1 encodes the retromer-associated receptor SORLA that functions in endosomal recycling. Rare variants in SORL1 have been associated with Alzheimers disease (AD) and rare pathogenic variants are estimated to occur in up to 2.75% of early onset AD patients and in 1.5% of unrelated late onset AD patients. While truncation mutations are observed almost exclusively in AD patients, it is currently unknown which among the hundreds of rare missense variants identified in SORL1, are pathogenic. Here we address this question by relying on SORLAs distinct molecular architecture. First, we completed a structure-guided sequence alignment for all the protein domains. Next, we identified proteins that contain domains homologous to those of SORLA, which include pathogenic variants for monogenic diseases. We identified the analogous domain positions of these variants in the SORLA protein sequence and showed that variants in these positions similarly impair SORL1, and lead to AD. Together, our findings represent a comprehensive compendium on SORLA protein variation and functional effects, which allowed us to prioritize SORL1 genetic variants into high or moderate priority mutations. We envision that this compendium will be used by clinical geneticists for assessing variants they identify in patients, allowing further development of diagnostic procedures and patient counseling strategies. Utimately, this compendium will inform investigations into the molecular mechanisms of endosomal recycling which will support the development of therapeutic treatment strategies for SORL1 variant-carrying patients.

biochemistry↗

bioRxiv2019

Cerebellar plasticity and associative memories are controlled by perineuronal nets

Perineuronal nets (PNNs) are assemblies of extracellular matrix molecules, which surround the cell body and dendrites of many types of neuron and regulate neural plasticity. PNNs are prominently expressed around neurons of the deep cerebellar nuclei (DCN) but their role in adult cerebellar plasticity and behavior is far from clear. Here we show that PNNs in the DCN are diminished during eyeblink conditioning (EBC), a form of associative motor learning that depends on DCN plasticity. When memories are fully acquired, PNNs are restored. Enzymatic digestion of PNNs in the DCN improves EBC learning, but intact PNNs are necessary for memory retention. At the structural level, PNN removal induces significant synaptic rearrangements in vivo, resulting in increased inhibition of DCN baseline activity in awake behaving mice. Together, these results demonstrate that PNNs are critical players in the regulation of cerebellar circuitry and function.

neuroscience↗