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Multiple repeat elements within the FAM21 tail link the WASH actin regulatory complex to the retromer
Abstract
Wiskott–Aldrich syndrome protein (WASPs) control actin dynamics in cellular processes, including cell motility, receptor-mediated endocytosis, bacterial invasion, and vesicular trafficking. We demonstrated that WASH, a recently identified WASP family protein, colocalizes on endosomal subdomains with the cargo-selective complex (CSC) of the retromer, where it regulates retrograde sorting from endosomes in an actin-dependent manner. However, the mechanism of WASH recruitment to these retromer-enriched endosomal subdomains is unclear. Here we show that a component of the WASH regulatory complex (SHRC), FAM21, which contains 21 copies of a novel L-F-[D/E]3-10-L-F motif, directly interacts with the retromer CSC protein VPS35. Endosomal localization of FAM21 is VPS35 dependent and relies on multivalency of FAM21 repeat elements. Using a combination of pull-down assays and isothermal calorimetry, we demonstrate that individual repeats can bind CSC, and binding affinity varies among different FAM21 repeats. A high-affinity repeat can be converted into a low-affinity one by mutation of a hydrophobic residue within the motif. These in vitro data mirror the localization of FAM21 to retromer-coated vesicles in cells. We propose that multivalency enables FAM21 to sense the density of retromer on membranes, allowing coordination of SHRC recruitment, and consequent actin polymerization, with retromer sorting domain organization/maturation.
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WASH complex is localised to endosomes via a retromer-independent mechanism that may rely on direct ability of WASH to bind lipids.
“From these data, we propose a working model (Figure 4H) where the WASH complex is localised to endosomes via a retromer-independent mechanism that may, in part, rely on the direct ability of the WASH complex to bind lipids21, 23.”
From Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling (2017) · cites this paper as [21]
The Results section ('VPS35 regulates FAM21 and SHRC localization'; page unavailable) reports that suppressing the retromer component VPS35 dissociated FAM21 from endosomal membranes and concludes that WASH-complex localization to retromer-enriched endosomal subdomains is VPS35 dependent. This contradicts the claimed retromer-independent localization mechanism. The cited passages also do not establish direct lipid binding by the WASH complex. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredVPS35 binds to multiple LFa repeats in FAM21 tail and this interaction is suggested to be sufficient and essential to recruit WASH complex to endosomes.
“The retromer subunit VPS35 binds to multiple LFa repeats in the FAM21 tail and this interaction is suggested to be sufficient and essential to recruit the WASH complex to endosomes20, 21.”
From Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling (2017) · cites this paper as [21]
CCC is a multiprotein assembly comprising CCDC22, CCDC93, and COMMD proteins.
“Another crucial component involved in endosomal recycling is the COMMD/CCDC22/CCDC93 complex14 (CCC), a multiprotein assembly that has co-evolved with the WASH complex.”
From Structural organization of the retriever–CCC endosomal recycling complex (2024) · cites this paper as [14]
The Introduction describes the WASH regulatory complex and a separate retromer cargo-selective complex (CSC), but does not describe the CCC complex. Searches for COMMD, CCDC22, and CCC’s proposed relationship to WASH found no passage identifying CCC’s components or addressing its co-evolution with WASH. (LLM, conf=0.77)
Experimental — accuracy not yet measuredCCC subunits form a large conserved protein assembly renamed Commander.
“Other studies examining protein assemblies across distinct organisms confirmed that CCC subunits (CCDC22, CCDC93 and 10 COMMD proteins) form a large conserved protein assembly as had been originally described14 and renamed the assembly as Commander28.”
From Structural organization of the retriever–CCC endosomal recycling complex (2024) · cites this paper as [14]
The Introduction describes the WASH regulatory complex and retromer, not a CCC assembly. Searches of our full-text copy for CCDC22, CCDC93, COMMD proteins, and Commander found no passage addressing the claimed assembly or its renaming. (LLM, conf=0.76)
Experimental — accuracy not yet measuredPrior work identified the significance of the N-terminal sequences of the CCDC22-CCDC93 dimer in binding to COMMD proteins.
“While our models had unraveled the roles of the coiled coils at the C-termini of CCDC22-CCDC93 heterodimer in the binding to Retriever and DENND10, respectively, prior work had identified the significance of the N-terminal sequences of the CCDC22-CCDC93 dimer in binding to COMMD proteins14.”
From Structural organization of the retriever–CCC endosomal recycling complex (2024) · cites this paper as [14]
The Introduction discusses FAM21 within the WASH regulatory complex, and the Results sections examine FAM21 binding to retromer CSC. Our copy does not address whether the N-terminal sequences of CCDC22–CCDC93 bind COMMD proteins (searched: CCDC22, CCDC93, COMMD, and N-terminal binding). Page numbers were not available in the supplied passages. (LLM, conf=0.76)
Experimental — accuracy not yet measured
The CCDC22-CCDC93 heterodimer is destabilized whenever any given COMMD protein is knocked out in cells or tissues.
“This could explain why the CCDC22-CCDC93 heterodimer is destabilized whenever any given COMMD protein is knocked out in cells or in tissues14,25,46.”
From Structural organization of the retriever–CCC endosomal recycling complex (2024) · cites this paper as [14]
The Results section on FAM21 motif mutagenesis examines FAM21 binding to the retromer cargo-selective complex, not the stability of a CCDC22–CCDC93 heterodimer. Searches for CCDC22, CCDC93, COMMD knockout, and destabilization found no passage in our copy addressing the claimed effect in cells or tissues. No page numbers were available for these passages. (LLM, conf=0.75)
Experimental — accuracy not yet measuredWASH complex has inherent ability to bind phospholipids.
“While the mechanism for retromer-independent association of the WASH complex to endosomes remains to be established it is perhaps worth noting that the WASH complex has an inherent ability to bind to phospholipids21, 23.”
From Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling (2017) · cites this paper as [21]
The Introduction and Discussion describe WASH-complex recruitment to endosomal membranes through FAM21 binding retromer, but do not address whether the complex can bind phospholipids. Searches for phospholipid, lipid, and liposome binding found no passage establishing that ability. Retromer-mediated recruitment does not rule it out. (LLM, conf=0.73)
Experimental — accuracy not yet measuredFAM21 and WASH complex are recruited to endosomes through retromer-dependent and retromer-independent mechanisms.
“FAM21 and the WASH complex are therefore recruited to endosomes through retromer-dependent20, 21 and retromer-independent mechanism(s).”
From Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling (2017) · cites this paper as [21]
Direct binding of FAM21 to VPS35 is a major mechanism for the retromer-dependent association of the WASH complex to endosomes.
“Direct binding of FAM21 to VPS35 is a major mechanism for the retromer-dependent association of the WASH complex to endosomes (Gomez and Billadeau, 2009; Harbour et al., 2010; Jia et al., 2012).”
From Acute inactivation of retromer and ESCPE-1 leads to time-resolved defects in endosomal cargo sorting (2020) · cites this paper as Jia et al., 2012
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Citations
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“There, N-WASP controls actin dynamics, which is important for both membrane invagination and vesicle scission (Merrifield et al., 2005; Yarar et al., 2005).”
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Metadata
- Authors
- Jia, D., Gomez, T. S., Billadeau, D. D., & Rosen, M. K.
- Venue
- Molecular Biology of the Cell
- Published
- 2012-06-15
- Volume
- 23
- Issue
- 12
- Pages
- 2352-2361
- ISSN
- 1059-1524
- 1939-4586
- PMC
- PMC3374753
- Cited by
- 200
- References
- 2
- Language
- en
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