Crystal Structure of the SH3 Domain of ASAP1 in Complex with the Proline Rich Motif (PRM) of MICAL1 Reveals a Unique SH3/PRM Interaction Mode

Jia, Xuanyan; Lin, Leishu; Xu, Shun; Li, Lingxuan; Wei, Zhiyi; Yu, Cong; Niu, Fujun

doi:10.3390/ijms24021414

Cited by 7 publications

(6 citation statements)

References 53 publications

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“…Similar to what was revealed by Jia et al 45 , a unique "C-X-X-(D/E)" sequence in the R/Tloop of ASAP1-SH3 creates a negatively charged binding pocket (pocket III) for the lysine residue at position +2 of the gAnkB peptide. This C-X-X-(D/E) sequence is present in ASAP1, ASAP2, GRAF1, GRAF2, GRAF3 and SKAP1, but not in the SH3 domains of other proteins.…”

Section: Mechanisms Underlie the High Affinity And Specificity Of The...supporting

confidence: 72%

“…S1A), but does not exist in gAnkB’s paralog ankyrin-G or ankyrin-R, suggesting that ASAP1 is a specific gAnkB binder in animal brains. We further note that the binding between ASAP1 and gAnkB is the strongest interaction among all reported ASAP1-SH3 binding proteins 45 . In addition, strong binding between the SH3 domain of ASAP2, a homolog of ASAP1 that also identified in our AP-Mass, and gAnkB is also detected by ITC (Kd ∼68 nM; Fig.…”

Section: Resultsmentioning

confidence: 53%

“…APC has only one positively charged Lys at the +6 position and this Lys partially occupies the negatively charged flat surface of ASAP1 SH3 and the rest of the APC peptide turns away from the charged surface (Fig. 4B, 4D), again providing an explanation to the weaker binding of APC to ASAP1 45 . Interestingly, the residue at the +3 position of APC is a Ser instead of Pro (Fig.…”

Section: Resultsmentioning

confidence: 93%

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Arf GTPase-activating protein ASAP1 specifically binds to 440-kD ankyrin-B

Li,

Zhao,

et al. 2024

Preprint

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The 440-kD giant ankyrin-B (gAnkB) exclusively localizes to axons and is essential for axon development. However, proteins that specifically bind to gAnkB but not to other isoforms of ankyrins are poorly understood. Here, we discovered that an Arf GTPase-activating protein ASAP1 and ASAP2 specifically binds to a short and disordered sequence unique to gAnkB. Biochemical studies showed that the SH3 domain of ASAP1 binds to a 12-residue, positively charged peptide fragment from gAnkB. The high-resolution structure of the ASAP1-SH3 domain in complex with the gAnkB peptide revealed the mechanism underlying this non-canonical SH3 domain-mediated target recognition. Further structural and bioinformatic analysis revealed additional previously unknown ASAP1-SH3 binding partners including Clasp1 and Clasp2, both of which are well-known microtubule regulators. Among all known ASAP1-SH3 binders including those identified in the current study, gAnkB has the strongest affinity in binding to ASAP1. Our results suggest that ASAP1 may function together with gAnkB in regulating axonal cytoskeletons.

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Section: Mechanisms Underlie the High Affinity And Specificity Of The...supporting

confidence: 72%

Section: Resultsmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 93%

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Arf GTPase-activating protein ASAP1 specifically binds to 440-kD ankyrin-B

Li,

Zhao,

et al. 2024

Preprint

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“…Domain and motif analysis are techniques used to study the structure and function of gene/ proteins (Shen et al 2020 ). Several genes may share common domains, domain superfamilies, and motifs, participating in various cellular, biological, and molecular functions (Jia et al 2023 ). In the context of proteins, a domain is a distinct structural unit or region within the protein that has a specific function.…”

Section: Resultsmentioning

confidence: 99%

Network pharmacology and molecular docking: combined computational approaches to explore the antihypertensive potential of Fabaceae species

Shahzadi,

Yousaf,

Anjum

et al. 2024

Bioresour. Bioprocess.

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Hypertension is a major global public health issue, affecting quarter of adults worldwide. Numerous synthetic drugs are available for treating hypertension; however, they often come with a higher risk of side effects and long-term therapy. Modern formulations with active phytoconstituents are gaining popularity, addressing some of these issues. This study aims to discover novel antihypertensive compounds in Cassia fistula, Senna alexandrina, and Cassia occidentalis from family Fabaceae and understand their interaction mechanism with hypertension targeted genes, using network pharmacology and molecular docking. Total 414 compounds were identified; initial screening was conducted based on their pharmacokinetic and ADMET properties, with a particular emphasis on adherence to Lipinski's rules. 6 compounds, namely Germichrysone, Benzeneacetic acid, Flavan-3-ol, 5,7,3',4'-Tetrahydroxy-6, 8-dimethoxyflavon, Dihydrokaempferol, and Epiafzelechin, were identified as effective agents. Most of the compounds found non-toxic against various indicators with greater bioactivity score. 161 common targets were obtained against these compounds and hypertension followed by compound-target network construction and protein–protein interaction, which showed their role in diverse biological system. Top hub genes identified were TLR4, MMP9, MAPK14, AKT1, VEGFA and HSP90AA1 with their respective associates. Higher binding affinities was found with three compounds Dihydrokaempferol, Flavan-3-ol and Germichrysone, −7.1, −9.0 and −8.0 kcal/mol, respectively. The MD simulation results validate the structural flexibility of two complexes Flavan-MMP9 and Germich-TLR4 based on no. of hydrogen bonds, root mean square deviations and interaction energies. This study concluded that C. fistula (Dihydrokaempferol, Flavan-3-ol) and C. occidentalis (Germichrysone) have potential therapeutic active constituents to treat hypertension and in future novel drug formulation. Graphical Abstract

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“…Effector proteins, such as Rab8a-subfamily GTPases and Plexins, can locally activate MICALs by binding to the RBD 10,18,34 . Despite extensive studies on individual domain structures 19,31,[34][35][36][37][38][39][40] , the molecular mechanisms underlying the autoinhibition and activation of MICALs remain poorly understood due to the lack of structural information on full-length MICAL proteins.…”

Section: Mainmentioning

confidence: 99%

Autoinhibition and Activation Mechanisms for MICAL Monooxygenases in F-actin Disassembly

Wei,

Lin,

Dong

et al. 2024

Preprint

Self Cite

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MICAL (Molecule Interacting with CasL) proteins represent a unique family of actin regulators crucial for synapse development, membrane trafficking, and cytokinesis. Unlike classical actin regulators, MICAL proteins possess enzymatic activity, catalyzing the oxidation of specific residues within actin filaments to induce robust filament severing. The potent activity of MICAL proteins requires tight control to prevent extensive damage to the actin cytoskeleton. Due to limited structural information on full-length MICAL proteins, the molecular mechanisms governing MICAL autoinhibition and activation remain elusive. Here, we reported the cryo-EM structure of full-length MICAL1, unveiling a head-to-tail interaction that allosterically blocks enzymatic activity through the binding of the C-terminal Rab-binding domain (RBD) to the N-terminal monooxygenase domain. The structure also reveals the assembly of C-terminal domains via a tripartite interdomain interaction, stabilizing the inhibitory conformation of the RBD. Our structural, biochemical, and cellular analyses elucidate the transition from the autoinhibited to activated conformation of MICAL1 in response to Rab8-subfamily GTPase. Dual Rab-binding to the RBD induces the conformation rearrangement of the RBD and synergistically promotes the autoinhibition-to-activation transition, revealing intricate activity regulation mechanisms for MICAL proteins. Furthermore, our mutagenesis study of MICAL3 suggests a conserved autoinhibition and activation mechanism among MICAL proteins.

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Crystal Structure of the SH3 Domain of ASAP1 in Complex with the Proline Rich Motif (PRM) of MICAL1 Reveals a Unique SH3/PRM Interaction Mode

Cited by 7 publications

References 53 publications

Arf GTPase-activating protein ASAP1 specifically binds to 440-kD ankyrin-B

Arf GTPase-activating protein ASAP1 specifically binds to 440-kD ankyrin-B

Network pharmacology and molecular docking: combined computational approaches to explore the antihypertensive potential of Fabaceae species

Autoinhibition and Activation Mechanisms for MICAL Monooxygenases in F-actin Disassembly

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