Evolution of Functional Diversity in the Holozoan Tyrosine Kinome

Yeung, Wayland; Kwon, Annie; Taujale, Rahil; Bunn, Claire; Venkat, Aarya; Kannan, Natarajan

doi:10.1093/molbev/msab272

Cited by 22 publications

(22 citation statements)

References 89 publications

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“…A projection of archetypical kinase PKA-α reveals positive peaks for kinase-conserved motifs (Figure 3D). We observe similar peaks for HIPK2 which has a CMGC-specific insertion region towards the Cterminal of the kinase domain 40 and VEGFR1 which has the longDE insertion towards the center of the kinase domain 41 . These fast-evolving insertion regions correspond to negative peaks.…”

Section: Unsupervised Hierarchical Clustering Of the Protein Embeddin...supporting

confidence: 55%

An explainable unsupervised framework for alignment-free protein classification using sequence embeddings

Yeung¹,

Zhou²,

Mathew³

et al. 2022

Preprint

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Protein classification is a cornerstone of biology that relies heavily on alignment-based comparison of primary sequences. However, the systematic classification of large protein superfamilies is impeded by unique challenges in aligning divergent sequence datasets. We developed an alignment-free approach for sequence analysis and classification using embedding vectors generated from pre-trained protein language models that capture underlying protein structural-functional properties from unsupervised training on millions of biologically-observed sequences. We constructed embedding-based trees (with branch support) which depict hierarchical clustering of protein sequences and infer fast/slow evolving sites through interpretable sequence projections. Applied towards diverse protein superfamilies, embedding tree infers Casein Kinase 1 (CK1) as the basal protein kinase clade, identifies convergent functional motifs shared between divergent phosphatase folds, and infers evolutionary relationships between diverse radical S-Adenosyl-L-Methionine (SAM) enzyme families. Overall results indicate that embedding trees effectively capture global data structures, functioning as a general unsupervised approach for visualizing high-dimensional manifolds.

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Section: Unsupervised Hierarchical Clustering Of the Protein Embeddin...supporting

confidence: 55%

An explainable unsupervised framework for alignment-free protein classification using sequence embeddings

Yeung¹,

Zhou²,

Mathew³

et al. 2022

Preprint

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“…The Tec kinases, including Btk and Itk, constitute one of three families of cytoplasmic tyrosine kinases that contain a conserved SH3-SH2-kinase unit known as the Src module (Shah et al, 2018; Yeung et al, 2021). The other two kinase families that contain a Src module are the Src-family kinases and the Abl family.…”

Section: Resultsmentioning

confidence: 99%

Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2

Nocka

Groves

Kuriyan

2022

Preprint

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The Tec-family kinase Btk contains a lipid-binding Pleckstrin homology and Tec homology (PH22 TH) module connected by a proline-rich linker to a “Src module”, an SH2-SH3-kinase unit also found in Src-family kinases and Abl. We showed previously that Btk is activated by PH-TH dimerization, which is triggered on membranes by the phosphatidyl inositol phosphate PIP3, or in solution by hexakisinositol phosphate (IP6) (Wang et al. 2015, https://doi.org/10.7554/eLife.06074). We now report that the ubiquitous adaptor protein growth factor-receptor-bound protein 2 (Grb2) binds to and substantially increases the activity of PIP3- bound Btk on membranes. Using reconstitution on supported-lipid bilayers, we find that Grb2 can be recruited to membrane-bound Btk through interaction with the proline-rich linker in Btk. This interaction requires intact Grb2, containing both SH3 domains and the SH2 domain, but does not require that the SH2 domain be able to bind phosphorylated tyrosine residues – thus Grb2 bound to Btk is free to interact with scaffold proteins via the SH2 domain. We show that the Grb2-Btk interaction recruits Btk to scaffold-mediated signaling clusters in reconstituted membranes. Our findings indicate that PIP3-mediated dimerization of Btk does not fully activate Btk, and that Btk adopts an autoinhibited state at the membrane that is released by Grb2.

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“…Choanoflagellates have dynamic life histories and diverse kinases families that are not found in animals (9, 11, 53, 66). Whether kinases regulate additional aspects of choanoflagellate physiology, including life history transitions, remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…We sought to test whether small molecules could serve as useful tools to study kinase function in choanoflagellates, the closest living relatives of animals. Choanoflagellates possess homologs of diverse animal kinases (Figure S1) (9–11) and due to their phylogenetic placement are relevant for reconstructing the ancestral functions of animal cell signaling proteins (12, 13). Whether these predicted kinase homologs in choanoflagellates contribute to conserved physiological functions is not known.…”

Section: Introductionmentioning

confidence: 99%

“…Because aberrant kinase activity leads to human disease (14, 15), many tools to inhibit kinase activity and detect protein phosphorylation have been developed. These tools may also allow the study of choanoflagellate kinases, which have conserved features within the kinase active site (9, 11). Although targeted genome editing has been recently established in choanoflagellates (17), we inferred that the unique strengths of small molecules, including precise temporal control and discrete inhibition of enzymatic activity (18), might more readily reveal the physiological relevance of kinases, including those with essential functions, in choanoflagellates.…”

Section: Introductionmentioning

confidence: 99%

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A small molecule screen reveals the essentiality of p38 kinase for choanoflagellate cell proliferation

Rutaganira

Scopton

Dar

et al. 2022

Preprint

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Choanoflagellates, the closest living relatives of animals, express diverse animal genes and may thereby provide insights into the ancestral roles of genes essential for modern animal cell biology and development. While efforts to study conserved gene families in choanoflagellates have been constrained by the relative inefficiency of currently available genetic tools, small molecule approaches are readily available and may provide a complementary and scalable approach for studying protein function. To study the physiological roles of choanoflagellate kinases, including animal kinase homologs, we established a high-throughput platform to screen the model choanoflagellate Salpingoeca rosetta with a curated library of human kinase inhibitors. We identified 36 diverse kinase inhibitors that disrupt S. rosetta cell proliferation. By exploring structure-activity relationships of one inhibitor, sorafenib, we identified a p38 kinase as a stress-activated regulator of cell proliferation in S. rosetta. This finding indicates a conserved p38 function between choanoflagellates, animals and fungi. Moreover, this study demonstrates that existing kinase inhibitors can serve as powerful tools to examine the ancestral roles of kinases that regulate modern animal development.

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Evolution of Functional Diversity in the Holozoan Tyrosine Kinome

Cited by 22 publications

References 89 publications

An explainable unsupervised framework for alignment-free protein classification using sequence embeddings

An explainable unsupervised framework for alignment-free protein classification using sequence embeddings

Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2

A small molecule screen reveals the essentiality of p38 kinase for choanoflagellate cell proliferation

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