CYRI (FAM49) proteins are local inhibitors of Scar/WAVE induced lamellipodia that bind directly to active Rac1

AbstractActin-based protrusions driving cell migration are reinforced through positive feedback, but it is unclear how the cell restricts the eventual size of a protrusion or limits positive signals to cause splitting or retraction. We have identified an evolutionarily conserved regulator of the protrusion machinery, which we name CYRI (CYFIP-related Rac interacting) protein. CYRI shows sequence similarity to the Scar/WAVE complex member CYFIP in a Domain of Unknown Function, DUF1394. CYRI binds specifically to activated Rac1 via a common motif shared with CYFIP, establishing DUF1394 as a new Rac1 binding domain. CYRI-depleted cells have broad, Scar/WAVE-enriched lamellipodia and enhanced Rac1 signaling. Conversely, CYRI overexpression suppresses spreading and dramatically sharpens protrusions into unproductive needles. CYRI proteins use dynamic inhibition of Scar/WAVE induced actin to focus positive protrusion signals and regulate pseudopod complexity. CYRI behaves like a “local inhibitor” predicted and described in widely accepted mathematical models, but not previously identified in living cells.

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Crystal structure of the N-terminal domain of VqsR fromPseudomonas aeruginosaat 2.1 Å resolution

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x17009025 ◽

2017 ◽

Vol 73 (7) ◽

pp. 431-436

Author(s):

Qing He ◽

Kang Wang ◽

Tiantian Su ◽

Feng Wang ◽

Lichuan Gu ◽

...

Keyword(s):

Crystal Structure ◽

Sequence Similarity ◽

Transcriptional Regulator ◽

Binding Domain ◽

Structural Comparison ◽

Homoserine Lactones ◽

Terminal Domain ◽

C Terminus ◽

Common Motif ◽

The Common

VqsR is a quorum-sensing (QS) transcriptional regulator which controls QS systems (las,rhlandpqs) by directly downregulating the expression ofqscRinPseudomonas aeruginosa. As a member of the LuxR family of proteins, VqsR shares the common motif of a helix–turn–helix (HTH)-type DNA-binding domain at the C-terminus, while the function of its N-terminal domain remains obscure. Here, the crystal structure of the N-terminal domain of VqsR (VqsR-N; residues 1–193) was determined at a resolution of 2.1 Å. The structure is folded into a regular α–β–α sandwich topology, which is similar to the ligand-binding domain (LBD) of the LuxR-type QS receptors. Although their sequence similarity is very low, structural comparison reveals that VqsR-N has a conserved enclosed cavity which could recognize acyl-homoserine lactones (AHLs) as in other LuxR-type AHL receptors. The structure suggests that VqsR could be a potential AHL receptor.

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Faculty Opinions recommendation of A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signalling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1027193.342128 ◽

2005 ◽

Author(s):

Carole Parent

Keyword(s):

Binding Domain ◽

Evolutionarily Conserved

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An Approach to Cell Motility as a Key Mechanism in Oncology

Cancers ◽

10.3390/cancers13143576 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3576

Author(s):

José I. López ◽

Ildefonso M. De la Fuente

Keyword(s):

Cell Migration ◽

Cell Motility ◽

Living Cells ◽

Inherent Characteristic ◽

Survival And Development ◽

Fundamental Mechanism

Motility is an inherent characteristic of living cells manifesting cell migration, a fundamental mechanism of survival and development [...]

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Lamellipodin and the Scar/WAVE complex cooperate to promote cell migration in vivo

The Journal of Cell Biology ◽

10.1083/jcb.201304051 ◽

2013 ◽

Vol 203 (4) ◽

pp. 673-689 ◽

Cited By ~ 64

Author(s):

Ah-Lai Law ◽

Anne Vehlow ◽

Maria Kotini ◽

Lauren Dodgson ◽

Daniel Soong ◽

...

Keyword(s):

Cell Migration ◽

Neural Crest ◽

Neural Crest Cell ◽

Direct Interaction ◽

Dependent Manner ◽

Border Cell ◽

Promote Cell Migration ◽

Wave Complex

Cell migration is essential for development, but its deregulation causes metastasis. The Scar/WAVE complex is absolutely required for lamellipodia and is a key effector in cell migration, but its regulation in vivo is enigmatic. Lamellipodin (Lpd) controls lamellipodium formation through an unknown mechanism. Here, we report that Lpd directly binds active Rac, which regulates a direct interaction between Lpd and the Scar/WAVE complex via Abi. Consequently, Lpd controls lamellipodium size, cell migration speed, and persistence via Scar/WAVE in vitro. Moreover, Lpd knockout mice display defective pigmentation because fewer migrating neural crest-derived melanoblasts reach their target during development. Consistently, Lpd regulates mesenchymal neural crest cell migration cell autonomously in Xenopus laevis via the Scar/WAVE complex. Further, Lpd’s Drosophila melanogaster orthologue Pico binds Scar, and both regulate collective epithelial border cell migration. Pico also controls directed cell protrusions of border cell clusters in a Scar-dependent manner. Taken together, Lpd is an essential, evolutionary conserved regulator of the Scar/WAVE complex during cell migration in vivo.

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Multi-level Mathematical Models for Cell Migration in Confined Environments

10.1007/978-981-16-4866-3_8 ◽

2021 ◽

pp. 124-140

Author(s):

Luigi Preziosi ◽

Marco Scianna

Keyword(s):

Cell Migration ◽

Mathematical Models ◽

Multi Level

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Mini-Workshop: Mathematical Models for Cancer Cell Migration

Oberwolfach Reports ◽

10.4171/owr/2014/19 ◽

2014 ◽

Vol 11 (2) ◽

pp. 1075-1109

Author(s):

Andreas Deutsch ◽

Thomas Hillen ◽

Christina Surulescu ◽

Michael Winkler

Keyword(s):

Cell Migration ◽

Mathematical Models ◽

Cancer Cell ◽

Cancer Cell Migration

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ACBD3 Interaction with TBC1 Domain 22 Protein Is Differentially Affected by Enteroviral and Kobuviral 3A Protein Binding

mBio ◽

10.1128/mbio.00098-13 ◽

2013 ◽

Vol 4 (2) ◽

Cited By ~ 35

Author(s):

Alexander L. Greninger ◽

Giselle M. Knudsen ◽

Miguel Betegon ◽

Alma L. Burlingame ◽

Joseph L. DeRisi

Keyword(s):

Hepatitis A Virus ◽

Rna Virus ◽

Affinity Purification ◽

Binding Domain ◽

Aichi Virus ◽

Rab Gtpase ◽

Class Iii ◽

Gtpase Activating Proteins ◽

Evolutionarily Conserved ◽

Phosphatidylinositol 4

ABSTRACT Despite wide sequence divergence, multiple picornaviruses use the Golgi adaptor acyl coenzyme A (acyl-CoA) binding domain protein 3 (ACBD3/GCP60) to recruit phosphatidylinositol 4-kinase class III beta (PI4KIIIβ/PI4KB), a factor required for viral replication. The molecular basis of this convergent interaction and the cellular function of ACBD3 are not fully understood. Using affinity purification-mass spectrometry, we identified the putative Rab33 GTPase-activating proteins TBC1D22A and TBC1D22B as ACBD3-interacting factors. Fine-scale mapping of binding determinants within ACBD3 revealed that the interaction domains for TBC1D22A/B and PI4KB are identical. Affinity purification confirmed that PI4KB and TBC1D22A/B interactions with ACBD3 are mutually exclusive, suggesting a possible regulatory mechanism for recruitment of PI4KB. The C-terminal Golgi dynamics (GOLD) domain of ACBD3 has been previously shown to bind the 3A replication protein from Aichi virus. We find that the 3A proteins from several additional picornaviruses, including hepatitis A virus, human parechovirus 1, and human klassevirus, demonstrate an interaction with ACBD3 by mammalian two-hybrid assay; however, we also find that the enterovirus and kobuvirus 3A interactions with ACBD3 are functionally distinct with respect to TBC1D22A/B and PI4KB recruitment. These data reinforce the notion that ACBD3 organizes numerous cellular functionalities and that RNA virus replication proteins likely modulate these interactions by more than one mechanism. IMPORTANCE Multiple viruses use the same Golgi protein (ACBD3) to recruit the lipid kinase phosphatidylinositol 4-kinase class III beta (PI4KB) in order to replicate. We identify a new binding partner of ACBD3 in the evolutionarily conserved Rab GTPase-activating proteins (RabGAPs) TBC1D22A and -B. Interestingly, TBC1D22A directly competes with PI4KB for binding to the same location of ACBD3 by utilizing a similar binding domain. Different viruses are able to influence this interaction through distinct mechanisms to promote the association of PI4KB with ACBD3. This work informs our knowledge of both the physical interactions of the proteins that help maintain metazoan Golgi structure and how viruses subvert these evolutionarily conserved interactions for their own purposes.

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Identification of human proteins functionally conserved with the yeast putative adaptors ADA2 and GCN5.

Molecular and Cellular Biology ◽

10.1128/mcb.16.2.593 ◽

1996 ◽

Vol 16 (2) ◽

pp. 593-602 ◽

Cited By ~ 120

Author(s):

R Candau ◽

P A Moore ◽

L Wang ◽

N Barlev ◽

C Y Ying ◽

...

Keyword(s):

Transcriptional Activation ◽

Sequence Similarity ◽

Adaptor Proteins ◽

Yeast Two Hybrid ◽

Yeast Saccharomyces Cerevisiae ◽

Activation Domains ◽

Evolutionarily Conserved ◽

Human Proteins ◽

Two Hybrid

Transcriptional adaptor proteins are required for full function of higher eukaryotic acidic activators in the yeast Saccharomyces cerevisiae, suggesting that this pathway of activation is evolutionarily conserved. Consistent with this view, we have identified possible human homologs of yeast ADA2 (yADA2) and yeast GCN5 (yGCN5), components of a putative adaptor complex. While there is overall sequence similarity between the yeast and human proteins, perhaps more significant is conservation of key sequence features with other known adaptors. We show several functional similarities between the human and yeast adaptors. First, as shown for yADA2 and yGCN5, human ADA2 (hADA2) and human GCN5 (hGCN5) interacted in vivo in a yeast two-hybrid assay. Moreover, hGCN5 interacted with yADA2 in this assay, suggesting that the human proteins form similar complexes. Second, both yADA2 and hADA2 contain cryptic activation domains. Third, hGCN5 and yGCN5 had similar stabilizing effects on yADA2 in vivo. Furthermore, the region of yADA2 that interacted with yGCN5 mapped to the amino terminus of yADA2, which is highly conserved in hADA2. Most striking, is the behavior of the human proteins in human cells. First, GAL4-hADA2 activated transcription in HeLa cells, and second, either hADA2 or hGCN5 augmented GAL4-VP16 activation. These data indicated that the human proteins correspond to functional homologs of the yeast adaptors, suggesting that these cofactors play a key role in transcriptional activation.

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