Turchetto, S. | bioRxiv Science

bioRxiv2026

A Protein Language Model Reveals Organellar Calcium ATPases at Neuronal Synapses

The synapse between neurons hosts the protein machinery for information transfer and storage in the brain. Its local proteome, however, contains many proteins with unclear roles for synaptic function. To glean hypotheses from this local proteome, we developed Synapse Gigamapper (SyGi), a protein language model for predicting protein localization at synapses. SyGi identified 152 amino-acid motifs that are indicative of localization at excitatory or inhibitory synapses and revealed >100 candidate constituents from key cellular pathways. Among these candidates is the endoplasmic reticulum (ER)-bound ATPase for cytosolic Ca2+ clearance, SERCA. We found clusters of SERCA copies at excitatory synapses without ER. Rather, SERCA is colocalized with compartment-specific organelles at synapses-- the spine apparatus and synaptic vesicles. Taken together, SyGi is useful for exposing hidden components of neuronal synapses.

neuroscience↗

bioRxiv2020

ATP-Citrate lyase fuels axonal transport across species

Microtubule (MT)-based transport is an evolutionary conserved processed finely tuned by posttranslational modifications. Among them, α-tubulin acetylation, which is catalyzed by the α-tubulin N-acetyltransferase 1, Atat1, promotes the recruitment and processivity of molecular motors along MT tracks. However, the mechanisms that controls Atat1 activity remains poorly understood. Here, we show that a pool of vesicular ATP-citrate lyase Acly acts as a rate limiting enzyme to modulate Atat1 activity by controlling availability of Acetyl-Coenzyme-A (Acetyl-CoA). In addition, we showed that Acly expression is reduced upon loss of Elongator activity, further connecting Elongator to Atat1 in the pathway regulating α-tubulin acetylation and MT-dependent transport in projection neurons, across species. Remarkably, comparable defects occur in fibroblasts from Familial Dysautonomia (FD) patients bearing an autosomal recessive mutation in the gene coding for the Elongator subunit ELP1. Our data may thus shine new light on the pathophysiological mechanisms underlying FD.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cell biology↗