A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations

Paesmans, Jone; Martin, Ella; Deckers, Babette; Berghmans, Marjolijn; Sethi, Ritika; Loeys, Yannick; Pardon, Els; Steyaert, Jan; Verstreken, Patrik; Galicia, Christian; Versées, Wim

doi:10.7554/elife.64922

Cited by 11 publications

(6 citation statements)

References 65 publications

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“…We wondered whether the loss in activity in Inpp5kb could be caused by changes in amino acids identified to be critical for the catalytic activity of INPP5K. Basing this analysis on the available crystal structures of other Type II inositol phosphate 5-phosphatases, INPP5B and SYNJ1 (Paesmans et al, 2020; Trésaugues et al, 2014), we found that all sites were conserved in Inpp5ka and Inpp5kb and there were no major changes that could explain differences in activity (asterisks in Fig. 1 ).…”

Section: Resultsmentioning

confidence: 97%

Duplicated zebrafish (Danio rerio) inositol phosphatases inpp5ka and inpp5kb diverged in expression pattern and function

Shukla

Gural

Cauley

et al. 2022

Preprint

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One hurdle in the development of zebrafish models of human disease is the presence of multiple zebrafish orthologs resulting from whole genome duplication in teleosts. Mutations in Inositol polyphosphate 5-phosphatase K (INPP5K) lead to a syndrome characterized by variable presentation of intellectual disability, brain abnormalities, cataracts, muscle disease, and short stature. INPP5K is a phosphatase acting at position 5 of phosphoinositides to control their homeostasis and is involved in insulin signaling, cytoskeletal regulation, and protein trafficking. Previously, our group and others have replicated the human phenotypes in zebrafish knockdown models by targeting both INPP5K orthologs inpp5ka and inpp5kb. Here, we show that inpp5ka is the more closely related orthologue to human INPP5K. While both inpp5ka and inpp5kb mRNA expression levels follow a similar trend in the developing head, eyes, and tail, inpp5ka is much more abundantly expressed in these tissues than inpp5kb. In situ hybridization revealed a similar trend, also showing unique localization of inpp5kb in the pineal gland indicating different transcriptional regulation. We also found that inpp5kb has lost its catalytic activity against its preferred substrate, PtdIns(4,5)P2. Since most human mutations are missense changes disrupting phosphatase activity, we propose that loss of inpp5ka alone can be targeted to recapitulate the human presentation. In addition, we show that the function of inpp5kb has diverged from inpp5ka and may play a novel role in the zebrafish.

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Section: Resultsmentioning

confidence: 97%

Duplicated zebrafish (Danio rerio) inositol phosphatases inpp5ka and inpp5kb diverged in expression pattern and function

Shukla

Gural

Cauley

et al. 2022

Preprint

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“…Synaptojanin (SYNJ1 ) encodes a brain-specific polyphosphoinositide phosphatase containing two consecutive phosphatase domains and playing an important role in late stages of clathrin-mediated endocytosis [ 123 ].…”

Section: Resultsmentioning

confidence: 99%

Pediatric-Onset Epilepsy and Developmental Epileptic Encephalopathies Followed by Early-Onset Parkinsonism

Spagnoli

Fusco

Pisani

2023

IJMS

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Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10–15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and the 2017 ILAE epilepsies classification, we performed a literature review in PubMed. A few discrete presentations can be identified: Parkinsonism as a late manifestation of complex neurodevelopmental disorders, characterized by developmental and epileptic encephalopathies (DE-EE), with multiple, refractory seizure types and severely abnormal EEG characteristics, with or without preceding hyperkinetic MD; Parkinsonism in the context of syndromic conditions with unspecific reduced seizure threshold in infancy and childhood; neurodegenerative conditions with brain iron accumulation, in which childhood DE-EE is followed by neurodegeneration; and finally, monogenic juvenile Parkinsonism, in which a subset of patients with intellectual disability or developmental delay (ID/DD) develop hypokinetic MD between 10 and 30 years of age, following unspecific, usually well-controlled, childhood epilepsy. This emerging group of genetic conditions leading to epilepsy or DE-EE in childhood followed by juvenile Parkinsonism highlights the need for careful long-term follow-up, especially in the context of ID/DD, in order to readily identify individuals at increased risk of later Parkinsonism.

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“…S19 ). These structures play an important role in mediating anchorage to the plasma membrane and substrate recognition and binding ( 42 – 45 ), suggesting that hydrophobic spine-like structures are common regulatory structures governing the catalytic activity of many phosphoinositide phosphatases.…”

Section: Resultsmentioning

confidence: 99%

Interaction between S4 and the phosphatase domain mediates electrochemical coupling in voltage-sensing phosphatase (VSP)

Mizutani

Kawanabe

Jinno

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Voltage-sensing phosphatase (VSP) consists of a voltage sensor domain (VSD) and a cytoplasmic catalytic region (CCR), which is similar to phosphatase and tensin homolog (PTEN). How the VSD regulates the innate enzyme component of VSP remains unclear. Here, we took a combined approach that entailed the use of electrophysiology, fluorometry, and structural modeling to study the electrochemical coupling in Ciona intestinalis VSP. We found that two hydrophobic residues at the lowest part of S4 play an essential role in the later transition of VSD-CCR coupling. Voltage clamp fluorometry and disulfide bond locking indicated that S4 and its neighboring linker move as one helix (S4-linker helix) and approach the hydrophobic spine in the CCR, a structure located near the cell membrane and also conserved in PTEN. We propose that the hydrophobic spine operates as a hub for translating an electrical signal into a chemical one in VSP.

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A structure of substrate-bound Synaptojanin1 provides new insights in its mechanism and the effect of disease mutations

Cited by 11 publications

References 65 publications

Duplicated zebrafish (Danio rerio) inositol phosphatases inpp5ka and inpp5kb diverged in expression pattern and function

Duplicated zebrafish (Danio rerio) inositol phosphatases inpp5ka and inpp5kb diverged in expression pattern and function

Pediatric-Onset Epilepsy and Developmental Epileptic Encephalopathies Followed by Early-Onset Parkinsonism

Interaction between S4 and the phosphatase domain mediates electrochemical coupling in voltage-sensing phosphatase (VSP)

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