CEP57

CEP57 is a multidomain coiled-coil centrosomal scaffold protein that nucleates and stabilizes microtubules, maintains centriole engagement, and connects kinetochores to spindle assembly checkpoint signaling. Its N-terminal domain anchors the protein to the proximal centriole where it forms a ring-like complex with CEP63 and CEP152, while the C-terminal leucine zipper domain directly binds, nucleates, and bundles microtubules; liquid-liquid phase separation driven by its NTD, CTD, and a polybasic LMN motif concentrates tubulin to catalyze microtubule nucleation, with CEP63 acting as a negative regulator of this condensation (PMID:38857398, PMID:18294141, PMID:23333316). CEP57 binds the PACT domain of pericentrin to organize pericentriolar material and, together with CEP57L1, maintains centriole engagement through interphase and mitosis in a Plk1-regulated manner; at kinetochores it bridges the KMN network component Mis12 to Mad1–Mad2, thereby promoting spindle assembly checkpoint signaling and accurate chromosome segregation (PMID:30804344, PMID:33492359, PMID:26743940). Biallelic loss-of-function mutations in CEP57 cause mosaic variegated aneuploidy syndrome, characterized by premature centriole disengagement, centrosome amplification, and constitutional aneuploidies (PMID:21552266, PMID:30035751).

1. 2003 High

   The initial molecular function of CEP57 (Translokin) was established as an intracellular trafficking factor for FGF-2, revealing that a centrosome-associated protein could also direct cytoplasmic cargo toward the nucleus.

   Evidence Co-immunoprecipitation, RNAi knockdown, FGF-1/FGF-2 chimera mapping, and NLS-rescue experiments in cultured cells

   PMID:12717444

   Open questions at the time

   • Structural basis of FGF-2 recognition unknown
   • Whether trafficking function is independent of centrosome localization untested
   • In vivo relevance of FGF-2 trafficking not demonstrated
2. 2007 High

   Xenopus CEP57 was shown to localize to kinetochores and interact with Mis12, Zwint, CLIP-170, and γ-tubulin, establishing a dual centrosome–kinetochore localization and a role in stable kinetochore–microtubule attachment.

   Evidence Immunodepletion from Xenopus egg extracts, Co-IP, in vitro kinetochore–microtubule binding assay, live imaging

   PMID:17803911

   Open questions at the time

   • Whether kinetochore function is conserved in mammalian cells was unknown
   • Direct versus bridged binding to kinetochore components not distinguished
   • Relationship to spindle checkpoint signaling unexplored
3. 2008 High

   Domain dissection revealed that CEP57's N-terminal coiled-coil mediates centrosome targeting and self-multimerization, while the C-terminal coiled-coil directly nucleates and bundles microtubules in vitro, defining the protein's two core biochemical activities.

   Evidence Domain truncation/overexpression, in vitro microtubule nucleation and bundling assays, nocodazole resistance assay

   PMID:18294141

   Open questions at the time

   • Molecular basis of multimerization unresolved
   • How the two domains coordinate in full-length protein unknown
   • In vivo contribution of each domain to centrosome integrity untested
4. 2009 Medium

   CEP57 was placed in two exclusive kinesin-containing complexes (with KIF3A/KIF3B) that govern bidirectional FGF-2 trafficking, explaining how FGF-2 is partitioned between nuclear translocation and unconventional secretion.

   Evidence Co-immunoprecipitation and interaction partner identification with functional trafficking assays

   PMID:19804566

   Open questions at the time

   • Whether these trafficking complexes operate at the centrosome or elsewhere unresolved
   • Stoichiometry and regulatory switches between the two complexes unknown
5. 2011 Medium

   CEP57 was shown to sequester cyclin D1 in the cytoplasm of quiescent cells, preventing Cdk4-dependent Rb phosphorylation and premature S-phase entry, expanding its functional repertoire beyond microtubule and trafficking biology to cell-cycle control.

   Evidence Co-IP, RNAi knockdown, overexpression, pRB phosphorylation and cell-cycle analysis

   PMID:21306487

   Open questions at the time

   • Whether cyclin D1 binding occurs at the centrosome or in the cytosol is unclear
   • Physiological relevance in vivo not tested
   • Relationship to the aneuploidy phenotype not explored
6. 2011 Medium

   Human genetic evidence linked biallelic CEP57 loss-of-function mutations to mosaic variegated aneuploidy syndrome, providing the first disease causality and placing centrosomal microtubule nucleation failure as the disease mechanism.

   Evidence Exome sequencing of MVA patients with identification of loss-of-function variants

   PMID:21552266

   Open questions at the time

   • Genotype–phenotype correlation across different mutations unknown
   • Relative contribution of centrosome versus kinetochore dysfunction to patient aneuploidy untested
7. 2012 High

   CEP57 was integrated into pericentriolar material organization through its interaction with NEDD1; depletion revealed PCM fragmentation, multipolar spindles, and weakened centrosomal microtubule assembly, demonstrating that CEP57 is essential for spindle pole integrity.

   Evidence Reciprocal Co-IP (CEP57–NEDD1), RNAi depletion, spindle and chromosome phenotyping, microtubule binding assay

   PMID:22508265

   Open questions at the time

   • Whether NEDD1 interaction is direct or mediated by γ-tubulin not resolved
   • Role of CEP57 in PCM expansion versus maintenance not distinguished
8. 2013 High

   Superresolution microscopy and chemical crosslinking revealed that CEP57, CEP63, and CEP152 form a ring-like complex at the proximal end of centrioles, providing the first structural context for how these proteins scaffold centriole duplication licensing.

   Evidence Selective chemical crosslinking, STED superresolution microscopy, systematic interaction analysis of 31 centrosomal proteins

   PMID:23333316

   Open questions at the time

   • Stoichiometry and assembly order of the ring unclear
   • Functional hierarchy among the three ring components not defined
9. 2013 High

   CEP57 was found at the central spindle and midbody during cytokinesis, where it recruits Tektin 1 and organizes midbody microtubules, establishing a post-mitotic function beyond centrosome biology.

   Evidence Immunofluorescence, RNAi depletion, cytokinesis failure assay, CEP57–Tektin 1 direct interaction

   PMID:23569207

   Open questions at the time

   • How CEP57 transitions from centrosome to central spindle is unknown
   • Relationship between midbody function and aneuploidy phenotype untested
10. 2016 High

    Human CEP57 was confirmed at kinetochores where it bridges Mis12 (KMN network) to Mad1, establishing it as a direct molecular link between kinetochore attachment and spindle assembly checkpoint activation; its microtubule-binding activity participates in timely Mad1 removal upon attachment.

    Evidence Co-IP (CEP57–Mis12, CEP57–Mad1), RNAi depletion with SAC signaling and chromosome segregation readouts in human cells

    PMID:26743940

    Open questions at the time

    • Whether CEP57's kinetochore role is independent of its centrosome function unclear
    • Structural basis of the Mis12–CEP57–Mad1 ternary interaction unresolved
11. 2018 High

    A mouse knock-in truncation model recapitulated MVA features—premature centriole disjunction, centrosome amplification, and high-rate chromosome missegregation—and revealed that CEP57 also functions in FGF2-mediated bone formation in vivo.

    Evidence Cep57T/T mouse model, MEF and patient fibroblast analysis, centrosome maturation assay, chromosome missegregation quantification

    PMID:30035751

    Open questions at the time

    • Which CEP57 domain is critical for bone phenotype not determined
    • Contribution of kinetochore versus centrosome defects to in vivo aneuploidy still ambiguous
12. 2019 High

    The mechanism of centriole engagement was resolved: CEP57 binds the PACT domain of pericentrin, and this interaction organizes PCM to prevent precocious centriole disengagement; MOPD pericentrin mutations that disrupt this interface phenocopy CEP57 loss.

    Evidence Co-IP mapping CEP57 to pericentrin PACT domain, RNAi, live imaging of centriole disengagement, MOPD patient cell analysis

    PMID:30804344

    Open questions at the time

    • Whether other PCM proteins also contribute to engagement maintenance untested
    • Structural details of CEP57–PACT interface unknown
13. 2021 High

    CEP57 and its paralog CEP57L1 were shown to cooperatively maintain centriole engagement throughout interphase, with co-depletion triggering Plk1-dependent precocious disengagement and centriole reduplication.

    Evidence Double RNAi depletion, live imaging, Plk1 inhibitor epistasis, centriole number quantification

    PMID:33492359

    Open questions at the time

    • How Plk1 triggers disengagement in the absence of CEP57/CEP57L1 unknown
    • Whether CEP57 and CEP57L1 occupy identical or distinct centriolar positions unclear
14. 2024 High

    CEP57 was shown to undergo liquid-liquid phase separation via its NTD, CTD, and a polybasic LMN motif; condensates concentrate tubulin to catalyze microtubule nucleation in vitro, with CEP63 restricting this activity, redefining the centrosomal scaffold as a phase-separated nucleation catalyst.

    Evidence In vitro LLPS reconstitution, in vitro microtubule nucleation assay, domain mutagenesis, competitive overexpression, rescue in CEP57-depleted cells

    PMID:38857398

    Open questions at the time

    • How LLPS is regulated in vivo during the cell cycle unknown
    • Whether LLPS contributes to kinetochore or midbody functions untested
    • How the LMN motif integrates with γ-tubulin ring complex-mediated nucleation unclear
15. 2024 Medium

    The crystal structure of the CEP57 C-terminal microtubule-binding domain revealed a leucine zipper with an adjacent microtubule-binding region, providing the first atomic-resolution view of the microtubule-scaffolding module.

    Evidence X-ray crystallography of the CEP57 C-terminal domain

    PMID:38699879

    Open questions at the time

    • Functional validation of individual structural elements not reported
    • No structure of full-length CEP57 or CEP57 in complex with microtubules available
16. 2026 Medium

    NuSAP was identified as a direct CEP57 interactor at centrioles; NuSAP-mediated tubulin stabilization is required for the initial loading of the CEP57–CEP63–CEP152 torus complex onto procentrioles, establishing an upstream assembly step.

    Evidence Super-resolution microscopy, TurboID proximity proteomics, Co-IP (CEP57–NuSAP), RNAi depletion with complex localization readout

    PMID:41616107

    Open questions at the time

    • Whether NuSAP–CEP57 interaction is direct or mediated by tubulin not fully resolved
    • Temporal regulation of NuSAP loading relative to centriole duplication licensing unknown

• Key unresolved questions include: how CEP57's phase separation is cell-cycle regulated, the structural basis of the CEP57–pericentrin PACT and CEP57–Mis12–Mad1 interfaces, the relative contributions of centrosome versus kinetochore dysfunction to MVA pathogenesis, and whether the trafficking and cyclin D1 sequestration functions operate through the same or distinct CEP57 pools.
• No cell-cycle-resolved LLPS regulation data
• No high-resolution structure of CEP57 in complex with pericentrin or kinetochore partners
• Centrosome versus kinetochore contribution to disease aneuploidy not separated