Evolution of modular intraflagellar transport from a coatomer-like progenitor

Dam, Teunis J. P. van; Townsend, Matthew J.; Turk, Martin; Schlessinger, Avner; Šali, Andrej; Field, Mark C.; Huynen, Martijn A.

doi:10.1073/pnas.1221011110

Cited by 148 publications

(199 citation statements)

References 40 publications

(27 reference statements)

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“…IFT38, IFT54, and IFT57 all share a similar predicted domain organization consisting of an N‐terminal calponin homology (CH) domain followed by C‐terminal coiled‐coil structure (Fig 1A) (Taschner et al , 2012; Schou et al , 2013). IFT172 and IFT80 are both predicted to contain two N‐terminal WD40 β‐propeller domains followed by α‐solenoid structure akin to the domain architecture observed for coatomer subunits (van Dam et al , 2013). Mutations in IFT172 and IFT80 were reported to result in skeletal pattering defects (Beales et al , 2007; Halbritter et al , 2013), and the two components interact genetically (Halbritter et al , 2013) albeit not physically in sucrose gradients (Lucker et al , 2005).…”

Section: Resultsmentioning

confidence: 98%

Intraflagellar transport proteins 172, 80, 57, 54, 38, and 20 form a stable tubulin‐binding IFT‐B2 complex

et al. 2016

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Intraflagellar transport (IFT) relies on the IFT complex and is required for ciliogenesis. The IFT‐B complex consists of 9–10 stably associated core subunits and six “peripheral” subunits that were shown to dissociate from the core structure at moderate salt concentration. We purified the six “peripheral” IFT‐B subunits of Chlamydomonas reinhardtii as recombinant proteins and show that they form a stable complex independently of the IFT‐B core. We suggest a nomenclature of IFT‐B1 (core) and IFT‐B2 (peripheral) for the two IFT‐B subcomplexes. We demonstrate that IFT88, together with the N‐terminal domain of IFT52, is necessary to bridge the interaction between IFT‐B1 and B2. The crystal structure of IFT52N reveals highly conserved residues critical for IFT‐B1/IFT‐B2 complex formation. Furthermore, we show that of the three IFT‐B2 subunits containing a calponin homology (CH) domain (IFT38, 54, and 57), only IFT54 binds αβ‐tubulin as a potential IFT cargo, whereas the CH domains of IFT38 and IFT57 mediate the interaction with IFT80 and IFT172, respectively. Crystal structures of IFT54 CH domains reveal that tubulin binding is mediated by basic surface‐exposed residues.

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Section: Resultsmentioning

confidence: 98%

Intraflagellar transport proteins 172, 80, 57, 54, 38, and 20 form a stable tubulin‐binding IFT‐B2 complex

et al. 2016

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“…This approach, which was previously found useful in identifying structural similarities among related proteins, 17,18 increases the confidence of domain assignments.…”

Section: In Silico Domain Predictionmentioning

confidence: 96%

Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome

et al. 2014

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Intellectual disability (ID) has an estimated prevalence of 2-3%. Due to its extreme heterogeneity, the genetic basis of ID remains elusive in many cases. Recently, whole exome sequencing (WES) studies revealed that a large proportion of sporadic cases are caused by de novo gene variants. To identify further genes involved in ID, we performed WES in 250 patients with unexplained ID and their unaffected parents and included exomes of 51 previously sequenced child-parents trios in the analysis. Exome analysis revealed de novo intragenic variants in SET domain-containing 5 (SETD5) in two patients. One patient carried a nonsense variant, and the other an 81 bp deletion located across a splice-donor site. Chromosomal microarray diagnostics further identified four de novo non-recurrent microdeletions encompassing SETD5. CRISPR/Cas9 mutation modelling of the two intragenic variants demonstrated nonsense-mediated decay of the resulting transcripts, pointing to a loss-of-function (LoF) and haploinsufficiency as the common disease-causing mechanism of intragenic SETD5 sequence variants and SETD5-containing microdeletions. In silico domain prediction of SETD5, a predicted SET domain-containing histone methyltransferase (HMT), substantiated the presence of a SET domain and identified a novel putative PHD domain, strengthening a functional link to well-known histone-modifying ID genes. All six patients presented with ID and certain facial dysmorphisms, suggesting that SETD5 sequence variants contribute substantially to the microdeletion 3p25.3 phenotype. The present report of two SETD5 LoF variants in 301 patients demonstrates a prevalence of 0.7% and thus SETD5 variants as a relatively frequent cause of ID.

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“…(C) Identification of protein homologs and co-occurrence with described cilia. Type of cilia (or absence thereof ) for each organism is based on a literature search (Carvalho-Santos et al, 2011;van Dam et al, 2013). Proteins with similarity to human PAM, furin, PC1 (also known as PCSK1), PC2 (also known as PCSK2), CPD and CPE were determined using NCBI Blastp (default parameters; Table S2 lists Uniprot IDs).…”

Section: Identification Of Pam Gene In Chlamydomonasmentioning

confidence: 99%

“…1C). Our analysis included organisms analyzed previously for the presence of cilia and key ciliary trafficking components, IFT-A, IFT-B and BBSomes (Carvalho-Santos et al, 2011;van Dam et al, 2013). These evolutionarily conserved coat-like proteins play crucial roles in ciliogenesis and localization of signaling proteins required for ciliary function.…”

Section: Identification Of Pam Gene In Chlamydomonasmentioning

confidence: 99%

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Early eukaryotic origins for cilia-associated bioactive peptide-amidating activity

Kumar

Blaby‐Haas

Merchant

et al. 2016

Journal of Cell Science

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Ciliary axonemes and basal bodies were present in the last eukaryotic common ancestor and play crucial roles in sensing and responding to environmental cues. Peptidergic signaling, generally considered a metazoan innovation, is essential for organismal development and homeostasis. Peptidylglycine α-amidating monooxygenase (PAM) is crucial for the last step of bioactive peptide biosynthesis. However, identification of a complete PAM-like gene in green algal genomes suggests ancient evolutionary roots for bioactive peptide signaling. We demonstrate that the Chlamydomonas reinhardtii PAM gene encodes an active peptide-amidating enzyme (CrPAM) that shares key structural and functional features with the mammalian enzyme, indicating that components of the peptide biosynthetic pathway predate multicellularity. In addition to its secretory pathway localization, CrPAM localizes to cilia and tightly associates with the axonemal superstructure, revealing a new axonemal enzyme activity. This localization pattern is conserved in mammals, with PAM present in both motile and immotile sensory cilia. The conserved ciliary localization of PAM adds to the known signaling capabilities of the eukaryotic cilium and provides a potential mechanistic link between peptidergic signaling and endocrine abnormalities commonly observed in ciliopathies.

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Evolution of modular intraflagellar transport from a coatomer-like progenitor

Cited by 148 publications

References 40 publications

Intraflagellar transport proteins 172, 80, 57, 54, 38, and 20 form a stable tubulin‐binding IFT‐B2 complex

Intraflagellar transport proteins 172, 80, 57, 54, 38, and 20 form a stable tubulin‐binding IFT‐B2 complex

Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome

Early eukaryotic origins for cilia-associated bioactive peptide-amidating activity

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