Differential Recognition Preferences of the Three Src Homology 3 (SH3) Domains from the Adaptor CD2-associated Protein (CD2AP) and Direct Association with Ras and Rab Interactor 3 (RIN3)

Rouka, E.; Simister, Philip C.; Janning, Melanie; Kumbrink, Joerg; Konstantinou, Tassos; Muniz, J.R.C.; Joshi, Dhira; O’Reilly, Nicola; Volkmer, Rudolf; Ritter, Brigitte; Knapp, Stefan; Delft, Frank von; Kirsch, Kathrin H.; Feller, Stephan M.

doi:10.1074/jbc.m115.637207

Cited by 34 publications

(39 citation statements)

References 71 publications

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“…For example, if a Lys (e.g., K114 in CD2AP) is replaced by a charge-neutral amino acid (e.g., Q 104) in CIN85, the structure difference may be minimal, but the difference in affinity for the interface at the binding partner might be rather large. This is underlined by a recent study employing flanking residue permutation arrays in the CD2AP-binding protein, ALIX, where selectivity could be achieved even between the three SH3 domains (28). Similar effects were also reported for the CIN85 SH3 domains (29).…”

Section: Discussionsupporting

confidence: 59%

The Pro-Oncogenic Adaptor CIN85 Acts as an Inhibitory Binding Partner of Hypoxia-Inducible Factor Prolyl Hydroxylase 2

et al. 2019

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The EGFR adaptor protein, CIN85, has been shown to promote breast cancer malignancy and hypoxiainducible factor (HIF) stability. However, the mechanisms underlying cancer promotion remain ill defined. Here we show that CIN85 is a novel binding partner of the main HIF-prolyl hydroxylase, PHD2, but not of PHD1 or PHD3. Mechanistically, the N-terminal SRC homology 3 domains of CIN85 interacted with the proline-arginine-rich region within the N-terminus of PHD2, thereby inhibiting PHD2 activity and HIF degradation. This activity is essential in vivo, as specific loss of the CIN85-PHD2 interaction in CRISPR/Cas9edited cells affected growth and migration properties, as well as tumor growth in mice. Overall, we discovered a previously unrecognized tumor growth checkpoint that is regulated by CIN85-PHD2 and uncovered an essential survival function in tumor cells by linking growth factor adaptors with hypoxia signaling. Significance: This study provides unprecedented evidence for an oxygen-independent mechanism of PHD2 regulation that has important implications in cancer cell survival.

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Section: Discussionsupporting

confidence: 59%

The Pro-Oncogenic Adaptor CIN85 Acts as an Inhibitory Binding Partner of Hypoxia-Inducible Factor Prolyl Hydroxylase 2

et al. 2019

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“…Similarly, the SLC24A4 locus harbors a small LD block with 46 SNPs that all reside within an intron of SLC24A4 . Previous work has implicated both SLC24A4 and the nearby Ras And Rab Interactor 3 ( RIN3 ) gene in this association but the true mediator remains unclear 44, 45 . Our multi-omic approach identifies a single SNP, rs10130373, which occurs within a microglia-specific peak, disrupts an SPI1 motif, and communicates specifically with the promoter of the RIN3 gene (Figure 4f-g).…”

Section: Resultsmentioning

confidence: 99%

Single-cell epigenomic identification of inherited risk loci in Alzheimer’s and Parkinson’s disease

Corces

Shcherbina

Kundu

et al. 2020

Preprint

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42Genome-wide association studies (GWAS) have identified thousands of variants associated with 43 disease phenotypes. However, the majority of these variants do not alter coding sequences, making 44 it difficult to assign their function. To this end, we present a multi-omic epigenetic atlas of the 45 adult human brain through profiling of the chromatin accessibility landscapes and three-46 dimensional chromatin interactions of seven brain regions across a cohort of 39 cognitively healthy 47 individuals. Single-cell chromatin accessibility profiling of 70,631 cells from six of these brain 48 regions identifies 24 distinct cell clusters and 359,022 cell type-specific regulatory elements, 49 capturing the regulatory diversity of the adult brain. We develop a machine learning classifier to 50 integrate this multi-omic framework and predict dozens of functional single nucleotide 51 polymorphisms (SNPs), nominating gene and cellular targets for previously orphaned GWAS loci. 52These predictions both inform well-studied disease-relevant genes, such as BIN1 in microglia for 53 Alzheimer's disease (AD) and reveal novel gene-disease associations, such as STAB1 in microglia 54 and MAL in oligodendrocytes for Parkinson's disease (PD). Moreover, we dissect the complex 55 inverted haplotype of the MAPT (encoding tau) PD risk locus, identifying ectopic enhancer-gene 56 contacts in neurons that increase MAPT expression and may mediate this disease association. This 57 work greatly expands our understanding of inherited variation in AD and PD and provides a 58 roadmap for the epigenomic dissection of noncoding regulatory variation in disease. 59 60 61 62Alzheimer's disease (AD) and Parkinson's disease (PD) affect ~50 and ~10 million individuals 63 world-wide, as two of the most common neurodegenerative disorders. Several large consortia have 64 assembled genome-wide association studies (GWAS) that associate genetic variants with clinical 65 diagnoses of probable AD dementia 1-4 or probable PD 5-7 , or with their characteristic pathologic 66 features. These efforts have led to the identification of dozens of potential risk loci for these 67 prevalent neurodegenerative diseases. One goal of these studies was to build more precise 68 molecular biomarkers of AD or PD, efforts that are beginning to yield encouraging results with 69 polygenic risk scores 8 . The other major goal was to gain deeper insight into the molecular 70 pathogenesis of disease and thereby inform novel therapeutic targets. Some of the risk loci contain 71 coding variants and so have credibility as putative disease mediators. However, most risk loci are 72 in noncoding regions and so it remains unclear if the nominated (often nearest) gene is the 73 functional disease-relevant gene, or if some other gene is involved 9 . Furthermore, even if the 74 nominated gene is a true positive, the noncoding risk locus might regulate additional genes. These 75 challenges remain a fundamental gap in interpreting the etiology of neurodegenerative diseases 76 and d...

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“…Structural Insights into Class III and IV Specificities Class III and class IV contain three domains each that prefer À6 RxxxxxP 0 (+) or 0 PxxxxR +5 (À) motifs, respectively, in which there is no specificity at the position that would be occupied by the proximal Pro residue in canonical class I or II domains, respectively ( Figures 3A and 3B). Notably, the six key positions forming the PXXP-binding site in these domains are conserved at the sequence level (Table S1), and the structures of CD2AP-1/3 and CD2AP-2/3 (Rouka et al, 2015) show that they can bind to class II peptides ( Figures 4D and 3E, respectively). However, in agreement with our results, peptide arrays and affinity assays (Rouka et al, 2015) have shown that 0 Px[P/ A] +2 xxR +5 (À) is the preferred binding motif for these domains and Pro +3 is not required for ligand recognition ( Figure 3B).…”

Section: Structural Insights Into Class I and Ii Specificitiesmentioning

confidence: 99%

“…Notably, the six key positions forming the PXXP-binding site in these domains are conserved at the sequence level (Table S1), and the structures of CD2AP-1/3 and CD2AP-2/3 (Rouka et al, 2015) show that they can bind to class II peptides ( Figures 4D and 3E, respectively). However, in agreement with our results, peptide arrays and affinity assays (Rouka et al, 2015) have shown that 0 Px[P/ A] +2 xxR +5 (À) is the preferred binding motif for these domains and Pro +3 is not required for ligand recognition ( Figure 3B). Given that the PXXP-binding site is conserved, it is not clear why these domains do not exhibit preference for a proximal Pro, but it is possible that substitutions within the hydrophobic core might alter peptide-binding specificity, as has been reported for some DNA-binding domains (Koulechova et al, 2015).…”

Section: Structural Insights Into Class I and Ii Specificitiesmentioning

confidence: 99%

Comprehensive Analysis of the Human SH3 Domain Family Reveals a Wide Variety of Non-canonical Specificities

et al. 2017

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SH3 domains are protein modules that mediate protein-protein interactions in many eukaryotic signal transduction pathways. The majority of SH3 domains studied thus far act by binding to proline-rich sequences in partner proteins, but a growing number of studies have revealed alternative recognition mechanisms. We have comprehensively surveyed the specificity landscape of human SH3 domains in an unbiased manner using peptide-phage display and deep sequencing. Based on ∼70,000 unique binding peptides, we obtained 154 specificity profiles for 115 SH3 domains, which reveal that roughly half of the SH3 domains exhibit non-canonical specificities and collectively recognize a wide variety of peptide motifs, most of which were previously unknown. Crystal structures of SH3 domains with two distinct non-canonical specificities revealed novel peptide-binding modes through an extended surface outside of the canonical proline-binding site. Our results constitute a significant contribution toward a complete understanding of the mechanisms underlying SH3-mediated cellular responses.

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Differential Recognition Preferences of the Three Src Homology 3 (SH3) Domains from the Adaptor CD2-associated Protein (CD2AP) and Direct Association with Ras and Rab Interactor 3 (RIN3)

Cited by 34 publications

References 71 publications

The Pro-Oncogenic Adaptor CIN85 Acts as an Inhibitory Binding Partner of Hypoxia-Inducible Factor Prolyl Hydroxylase 2

The Pro-Oncogenic Adaptor CIN85 Acts as an Inhibitory Binding Partner of Hypoxia-Inducible Factor Prolyl Hydroxylase 2

Single-cell epigenomic identification of inherited risk loci in Alzheimer’s and Parkinson’s disease

Comprehensive Analysis of the Human SH3 Domain Family Reveals a Wide Variety of Non-canonical Specificities

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