Structure of the SLy1 SAM homodimer reveals a new interface for SAM domain self-association

Kukuk, Laura; Dingley, Andrew J.; Granzin, Joachim; Nagel-Steger, Luitgard; Thiagarajan-Rosenkranz, Pallavi; Ciupka, Daniel; Hänel, Karen; Batra‐Safferling, Renu; Pacheco, Victor; Stoldt, Matthias; Pfeffer, Klaus; Beer‐Hammer, Sandra; Willbold, Dieter; Koenig, Bernd W.

doi:10.1038/s41598-018-37185-3

Cited by 15 publications

(24 citation statements)

References 77 publications

(100 reference statements)

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“…Additionally, asymmetric dimethylarginine (ADMA) is synthesized from the degradation of methylated proteins by L-Arg and is an effective endogenous non-selective NOS inhibitor. Oxidative stress can increase the level of ADMA by inactivating its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH) [ 116 , 204 , 205 ], therefore suppressing eNOS activity and inducing CEC dysfunction. A large number of studies have confirmed the involvement of ADMA in the occurrence of a variety of vascular diseases [ 82 , 206 , 207 , 208 ].…”

Section: Nos/no Pathway-involved Vad Therapiesmentioning

confidence: 99%

The Roles of Nitric Oxide Synthase/Nitric Oxide Pathway in the Pathology of Vascular Dementia and Related Therapeutic Approaches

Zhu

Hong

Yang

2021

IJMS

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Vascular dementia (VaD) is the second most common form of dementia worldwide. It is caused by cerebrovascular disease, and patients often show severe impairments of advanced cognitive abilities. Nitric oxide synthase (NOS) and nitric oxide (NO) play vital roles in the pathogenesis of VaD. The functions of NO are determined by its concentration and bioavailability, which are regulated by NOS activity. The activities of different NOS subtypes in the brain are partitioned. Pathologically, endothelial NOS is inactivated, which causes insufficient NO production and aggravates oxidative stress before inducing cerebrovascular endothelial dysfunction, while neuronal NOS is overactive and can produce excessive NO to cause neurotoxicity. Meanwhile, inflammation stimulates the massive expression of inducible NOS, which also produces excessive NO and then induces neuroinflammation. The vicious circle of these kinds of damage having impacts on each other finally leads to VaD. This review summarizes the roles of the NOS/NO pathway in the pathology of VaD and also proposes some potential therapeutic methods that target this pathway in the hope of inspiring novel ideas for VaD therapeutic approaches.

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Section: Nos/no Pathway-involved Vad Therapiesmentioning

confidence: 99%

The Roles of Nitric Oxide Synthase/Nitric Oxide Pathway in the Pathology of Vascular Dementia and Related Therapeutic Approaches

Zhu

Hong

Yang

2021

IJMS

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“…The canonical SAM domain fold consists of a five‐helix bundle (Figure ) and the C‐terminal α5 helix plays a pivotal role in driving SAM–SAM associations . A “tail to tail” model in which two C‐terminal α5 helices are contacting each other with a reciprocal reverse orientation has been observed in the crystal structure of oligomeric EphB2‐SAM, whereas SLy1‐SAM forms a symmetric homodimer stabilized by contacts between two α5 helices with the same orientation …”

Section: Introductionmentioning

confidence: 99%

Exploring the Ability of Cyclic Peptides to Target SAM Domains: A Computational and Experimental Study

et al. 2019

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Sterile alpha motif (SAM) domains are protein interaction modules with a helical fold. SAM–SAM interactions often adopt the mid‐loop (ML)/end‐helix (EH) model, in which the C‐terminal helix and adjacent loops of one SAM unit (EH site) bind the central regions of another SAM domain (ML site). Herein, an original strategy to attack SAM–SAM associations is reported. It relies on the design of cyclic peptides that target a region of the SAM domain positioned at the bottom side of the EH interface, which is thought to be important for the formation of a SAM–SAM complex. This strategy has been preliminarily tested by using a model system of heterotypic SAM–SAM interactions involving the erythropoietin‐producing hepatoma kinase A2 (EphA2) receptor and implementing a multidisciplinary plan made up of computational docking studies, experimental interaction assays (by NMR spectroscopy and surface plasmon resonance techniques) and conformational analysis (by NMR spectroscopy and circular dichroism). This work further highlights how only a specific balance between flexibility and rigidity may be needed to generate modulators of SAM–SAM interactions.

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“…HACS1 has a homolog SLy1/SASH3 that also participates in immune cell developmental programs, but cannot substitute for HACS1 despite having over 40% sequence identity. These functional distinctions appear to extend to the architecture of SLy1 since its SAM domain forms homodimers 44 . It is worth noting that the way in which the SLy1 SAM domain dimerizes is unique among the myriad of homo- and hetero-oligomeric SAM domain structures that have been described.…”

Section: Discussionmentioning

confidence: 93%

HACS1 signaling adaptor protein recognizes a motif in the paired immunoglobulin receptor B cytoplasmic domain

et al. 2020

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Hematopoietic adaptor containing SH3 and SAM domains-1 (HACS1) is a signaling protein with two juxtaposed protein–protein interaction domains and an intrinsically unstructured region that spans half the sequence. Here, we describe the interaction between the HACS1 SH3 domain and a sequence near the third immunoreceptor tyrosine-based inhibition motif (ITIM3) of the paired immunoglobulin receptor B (PIRB). From surface plasmon resonance binding assays using a mouse and human PIRB ITIM3 phosphopeptides as ligands, the HACS1 SH3 domain and SHP2 N-terminal SH2 domain demonstrated comparable affinities in the micromolar range. Since the PIRB ITIM3 sequence represents an atypical ligand for an SH3 domain, we determined the NMR structure of the HACS1 SH3 domain and performed a chemical shift mapping study. This study showed that the binding site on the HACS1 SH3 domain for PIRB shares many of the same amino acids found in a canonical binding cleft normally associated with polyproline ligands. Molecular modeling suggests that the respective binding sites in PIRB ITIM3 for the HACS1 SH3 domain and the SHP2 SH2 domain are too close to permit simultaneous binding. As a result, the HACS1-PIRB partnership has the potential to amalgamate signaling pathways that influence both immune and neuronal cell fate.

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Structure of the SLy1 SAM homodimer reveals a new interface for SAM domain self-association

Cited by 15 publications

References 77 publications

The Roles of Nitric Oxide Synthase/Nitric Oxide Pathway in the Pathology of Vascular Dementia and Related Therapeutic Approaches

The Roles of Nitric Oxide Synthase/Nitric Oxide Pathway in the Pathology of Vascular Dementia and Related Therapeutic Approaches

Exploring the Ability of Cyclic Peptides to Target SAM Domains: A Computational and Experimental Study

HACS1 signaling adaptor protein recognizes a motif in the paired immunoglobulin receptor B cytoplasmic domain

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