FIP200 (RB1CC1)

FIP200 — also called RB1CC1 (RB1-inducible coiled-coil 1) — is the largest subunit of the mammalian ULK1 autophagy initiation complex. At ~200 kDa and 1,594 amino acids (canonical isoform), it is one of the largest autophagy proteins identified in mammals. FIP200 functions as the structural scaffold of the complex: it anchors the entire four-subunit assembly (ULK1/ULK2 + ATG13 + ATG101 + FIP200) to sites of autophagosome nucleation and serves as the functional analog of the yeast Atg17–Atg31–Atg29 scaffold. Beyond general autophagy, FIP200 connects the ULK1 complex to selective autophagy cargo via direct binding of the cargo receptor p62 through its C-terminal Claw domain (aa 1494–1594), thereby coupling autophagy initiation to ubiquitin condensates ¹.

Identity

Field	Value
UniProt	Q8TDY2 (RCCI1_HUMAN)
NCBI Gene	9821
HGNC	15276
Gene symbol	RB1CC1
Preferred name	FIP200 (used throughout autophagy literature)
Full gene name	RB1 inducible coiled-coil 1
Protein length	1,594 amino acids (canonical isoform)
Molecular mass	~200 kDa (SDS-PAGE; calculated ~196 kDa)
Chromosome	8q11.23
Mouse ortholog	Rb1cc1 (one-to-one; ~79% sequence identity)
Yeast functional analog	Atg17 (structural/functional analog, not sequence ortholog)
GenAge entry	null needs-canonical-id — FIP200/RB1CC1 not found in GenAge human subset as of 2026-05-04

Naming note: “FIP200” derives from “FAK-family Interacting Protein of 200 kDa” — based on its original identification as a focal adhesion kinase-interacting protein. The HGNC-approved gene symbol is RB1CC1, reflecting the protein’s role in RB1-inducible coiled-coil formation. Both names are used; this wiki uses “FIP200” in body text per autophagy convention. No pathways/fip200.md exists; this protein page is the canonical [[fip200]] resolution.

Domain architecture

FIP200 is a large, extended coiled-coil scaffold. Its domain organization, from N- to C-terminus:

Domain / Region	Residues (human, approx.)	Function
N-terminal coiled-coil	~17–225	Mediates dimerization; required for complex integrity; region where FAK family members initially bind ²
LIR motif (central)	~585–588 (FEIV)	LC3-interacting region; contributes to LC3/Atg8-family docking during autophagosome membrane expansion; allows FIP200 membrane association unsourced — this residue range and motif identity is not established in Turco 2019 or Hara 2008; requires citation to a primary source characterizing the FIP200 LIR
Coiled-coil/IDR middle region	~226–1493	Largely uncharacterized; linker and regulatory scaffold; no stable fold assigned; no known enzymatic activity
Claw domain (C-terminal)	aa 1494–1594	Directly contacts p62 FIR motif; a claw-shaped globular domain (~100 aa); key site for selective autophagy cargo recognition and condensate-directed autophagosome formation ¹

Structural note: The Claw domain is a distinct C-terminal module (aa 1494–1594) identified by Turco et al. 2019 via X-ray crystallography (2.5–3.2 Å resolution) of FIP200 CTR fragments and biochemical pull-down assays ¹. It adopts a claw shape: a six-stranded antiparallel beta-sheet (the “palm”) with three flexible loops (“fingers”). The Claw binds the p62 FIR motif (aa 326–380 of p62) via a positively charged pocket, and this binding is mutually exclusive with p62’s binding to LC3B. The FIP200 CTR also contains an N-terminal Atg11 homology domain (aa ~1429–1493) whose binding partners in the mammalian context remain to be fully characterized ¹. Turco 2019 does not characterize NDP52/CLIR binding to the Claw, and does not structurally map ATG13 HORMA contacts to this domain — those remain unsourced claims requiring separate primary-source citations.

Function in the ULK1 initiation complex

FIP200 is an obligate, constitutive subunit of the four-subunit mammalian autophagy initiation complex:

Subunit	Gene	UniProt	Role
ULK1 (or ULK2)	ULK1 / ULK2	O75385	Ser/Thr kinase; integrates mTORC1 and AMPK signals
ATG13	ATG13	O75143	Scaffold; stabilizes ULK1; mTORC1 phosphorylation target; bridges ULK1 to FIP200
FIP200 (RB1CC1)	RB1CC1	Q8TDY2	Large scaffold; required for ULK1 stability, kinase activity, and membrane targeting; Claw domain binds p62 FIR at ubiquitin condensates ¹
ATG101	C12orf44	Q9BSB4	Stabilizes ATG13; WF finger recruits Atg8-family members; no direct FIP200 contact reported

FIP200 was identified as an essential ULK1-complex subunit in 2008 by Hara et al., who showed that FIP200 binds ULK1 directly, is required for ULK1 stability and kinase activity, and is necessary for starvation-induced autophagosome formation ². In parallel, Ganley et al. 2009 confirmed ULK1·ATG13·FIP200 as a functionally essential trimeric complex required for autophagy, prior to the addition of ATG101 as a fourth subunit in late 2009 ³.

FIP200’s structural role: Unlike ULK1 (kinase) or ATG13 (regulatory scaffold with multiple phospho-sites), FIP200 contributes primarily through its physical architecture. Its large coiled-coil scaffold positions the ULK1 complex at the endoplasmic reticulum / mitochondria-associated membranes where phagophores nucleate. FIP200 loss results in complete loss of ULK1 complex localization to punctate structures under starvation — consistent with a membrane-tethering or membrane-recognition role ².

FIP200 and ULK1 kinase activity: ATG13 and FIP200 additively stimulate ULK1 kinase activity. Either subunit alone provides partial stimulation; both together provide maximal activation ³. This additive kinase-stimulation relationship is distinct from simple scaffold function — FIP200 contributes to ULK1 catalytic competence, not merely complex localization.

Claw domain — cargo receptor recruitment for selective autophagy

A major function of FIP200 beyond bulk autophagy initiation is to directly bind selective autophagy cargo receptors:

p62/SQSTM1 FIR motif. Turco et al. 2019 demonstrated by X-ray crystallography and biochemical pull-down assays that the FIP200 Claw domain (aa 1494–1594) binds the FIR (FIP200-interacting region) motif of p62 (residues 326–380) directly via a positively charged pocket. p62 phosphorylation (S365, S366, S370) enhances the interaction ~2-fold. The interaction is mutually exclusive with p62’s LIR-mediated binding to LC3B, suggesting FIP200 is displaced from p62 as LC3 conjugation machinery arrives. This localizes ULK1 complex activity specifically to ubiquitin condensates marked by p62 ¹. needs-replication — independent structural confirmation from other groups not yet published.
NDP52/CALCOCO2 CLIR motif. FIP200 Claw binding to NDP52 is not characterized in Turco 2019. This claim requires a separate primary source citation. unsourced — remove or cite during next lint pass.
ATG13 HORMA contacts at the Claw. Turco 2019 does not characterize ATG13 HORMA binding to the FIP200 Claw domain. The Atg11 homology domain N-terminal to the Claw (aa ~1429–1493) may mediate interactions with HORMA-domain proteins, but this is not directly demonstrated in Turco 2019. unsourced — requires primary source.

The FIP200 Claw’s specific binding to p62-FIR means FIP200 functions not merely as a bulk autophagy scaffold but as a direct molecular coupler that recruits the ULK1 initiation complex to ubiquitin-condensate cargo marked by p62, prior to autophagosome membrane formation.

FIP200 and ATG16L1

A separate function of FIP200 distinguishes ULK1-complex-dependent from ULK1-independent autophagy. Gammoh et al. 2013 demonstrated that FIP200 directly interacts with ATG16L1 (a component of the ATG5–ATG12–ATG16L1 conjugation complex) through a short FIP200-binding domain (FBD) of ATG16L1 (residues 229–242) ⁴. This interaction recruits ATG16L1 to autophagosome precursors and is required for amino acid starvation-induced (ULK1-complex-dependent) autophagy but dispensable for glucose deprivation-induced (ULK1-complex-independent) autophagy. The FIP200–ATG16L1 interaction is direct (recombinant protein pull-down confirmed), independent of ATG5 and ATG13. This provides mechanistic insight into how the ULK1 complex specifically enables canonical, starvation-induced autophagosome biogenesis. needs-replication — this finding is from a single study; independent structural characterization of the FIP200–ATG16L1 interface at atomic resolution is lacking.

Discovery

The FIP200/RB1CC1 gene was originally characterized as a focal adhesion kinase-interacting protein regulating cell size and cell-cycle progression. Its role in autophagy was established in 2008 when Hara et al. (J Cell Biol) showed:

FIP200 co-immunoprecipitates with ULK1 (and ULK2) and is required for starvation-induced autophagosome formation in mammalian MEFs
FIP200 loss abolishes GFP-Atg5 and GFP-LC3 puncta formation under starvation — autophagosome formation is blocked, not merely delayed
FIP200 is required for ULK1 protein stability: ULK1 protein levels are lower in FIP200-/- MEFs, and ULK1 turns over faster by cycloheximide chase in the absence of FIP200
FIP200 is required for ULK1 punctate localization to the isolation membrane (phagophore) under starvation conditions
The C-terminal region (aa 829–1051) of ULK1 is required for FIP200 interaction and for ULK1 puncta formation

Note on neural cKO: Progressive neurodegeneration with ubiquitin/p62-positive inclusion bodies in Fip200 neural-specific conditional KO (Nestin-Cre) mice is reported by Komatsu et al. 2006 (Nature 441:880-884), not by Hara 2008. Hara 2008 cites this phenotype in its Discussion as evidence for FIP200’s essential autophagy role in post-mitotic neurons but does not perform neural cKO experiments.

This placed FIP200 as the mammalian functional analog of yeast Atg17 — the scaffold that positions Atg1 kinase at phagophore assembly sites — though FIP200 and Atg17 share no sequence homology.

Knockout phenotype

Germline Fip200-/- — embryonic lethality

Gan et al. 2006 generated Fip200-null (Rb1cc1-/-) mice via gene targeting and showed that homozygous deletion is embryonic lethal between E13.5 and E16.5 (no live KO embryos identified at E16.5 or thereafter), with multiple developmental defects including cardiac failure (ventricular dilation, sparse trabecular myocardium) and liver degeneration ⁵. Approximately 25% and 60% of homozygous embryos were found dead at E14.5 and E15.5 respectively (Table I of Gan 2006). This embryonic lethality precedes any aging-relevant analysis and is consistent with FIP200’s essential role in organ development.

Dimension	Status	Notes
Pathway conserved in humans?	yes	FIP200/RB1CC1 conserved; Claw domain contacts structurally confirmed in human cell lines
Phenotype conserved in humans?	partial	Germline KO lethal in mice; no human germline KO; cardiac/liver developmental roles inferred
Replicated in humans?	no	No human genetics data; indirect evidence via ULK1-complex disruption studies

needs-human-replication

Tissue-specific conditional KOs

Because germline deletion is lethal, tissue-specific conditional KOs have been generated:

Neural-specific Fip200 cKO (Nestin-Cre): Produces progressive neurodegeneration with ubiquitin/p62-positive inclusion bodies in neurons — phenotypically similar to Atg5/Atg7 conditional neural KOs, confirming FIP200 as an essential autophagy initiator in post-mitotic neurons (Komatsu et al. 2006, Nature 441:880-884 — not yet extracted as a study page; unsourced for this page until that study is ingested). This neurodegeneration phenotype is mechanistically relevant to aging: accumulation of protein aggregates and inclusion bodies is a hallmark feature of aged brains and age-related neurodegenerative diseases (see alzheimers-disease, parkinsons-disease, neurodegeneration).
Other tissues: Conditional KOs in additional tissues (liver, heart, skeletal muscle) have been generated by subsequent investigators, confirming that FIP200 is broadly required for tissue homeostasis in organs with high autophagy dependence. Data from these models are not directly cited in the primary sources of this page; unsourced — cite specific conditional-KO papers for liver/heart during next lint pass.

Regulation

FIP200 does not harbor the well-characterized mTORC1 or AMPK phosphorylation sites that regulate ULK1 (Ser758) or ATG13 (Ser258, Ser224). Instead, FIP200 is regulated primarily at the level of complex assembly and localization:

mTORC1 inhibition: When mTORC1 is inhibited by starvation or rapamycin, the ULK1 complex (including FIP200) redistributes from diffuse cytoplasmic distribution to discrete puncta on ER or mitochondria-associated membranes — a translocation that requires FIP200 for proper localization ².
ULK1 kinase dependency: FIP200 stability is partially ULK1-dependent; ULK1 loss leads to reduced FIP200 protein levels alongside ATG13 instability ².
No established FIP200 PTMs: No regulatory phosphorylation or ubiquitination sites on FIP200 are well-characterized as of 2026. unsourced — PhosphoSitePlus cross-check of FIP200 PTMs needed during next lint pass.

Role in aging

Autophagy initiation node — apex of a critical aging mechanism

FIP200 is required for the first step of canonical macroautophagy. Any mechanism that suppresses autophagy initiation during aging — including chronically elevated mTORC1 activity, reduced AMPK activity, or ULK1 complex destabilization — converges on FIP200’s functional context. The most pharmacologically validated longevity intervention in mammals (mTOR inhibition by rapamycin) restores ULK1-complex–mediated autophagy initiation, in which FIP200 is an essential scaffold. See mtor, ampk, ulk1, disabled-macroautophagy.

Neurodegeneration — aging-relevant KO phenotype

The neural Fip200 cKO phenotype (progressive inclusion body neurodegeneration) is directly relevant to aging biology because:

Protein aggregate accumulation (p62/ubiquitin-positive inclusions) mirrors what is observed in aged post-mitotic neurons in vivo
The phenotype is pathway-equivalent to Atg5/Atg7 neural cKOs — well-established autophagy-dependent neurodegeneration models

This positions FIP200 upstream of the same proteostasis maintenance axis that is lost in aged neurons and in age-related neurodegenerative diseases. needs-human-replication — no human FIP200 loss-of-function disease genetics established.

Selective autophagy failure — p62 condensate clearance

The FIP200 Claw domain’s direct binding to p62 means that FIP200 dysfunction would specifically impair selective clearance of ubiquitinated protein aggregates. p62 condensates that accumulate in aging tissues (liver, muscle, brain) require FIP200-dependent ULK1-complex recruitment for efficient clearance. If FIP200 expression or Claw domain function declines with age, selective autophagy of protein aggregates would be disproportionately impaired even before bulk autophagy flux becomes limiting. This is a mechanistic hypothesis with no direct supporting aged-tissue data yet. no-mechanism needs-replication

Pathway membership and cross-references

autophagy — FIP200 is the large structural scaffold of the ULK1 initiation complex, the apex of canonical macroautophagy; see that page for the full Stage 1–5 mechanism
mtor — mTORC1 suppresses the ULK1 complex activity that FIP200 scaffolds; FIP200 translocation to phagophore sites is inhibited under mTORC1-active conditions
ulk1 — kinase partner; FIP200 is required for ULK1 stability and localization; FIP200 and ATG13 together provide additive ULK1 kinase stimulation ³
atg13 — ATG13 bridges ULK1 to FIP200; the precise molecular surface on FIP200 that mediates ATG13 contact is not yet established in papers cited here (#gap/unsourced); the ATG13–FIP200 interaction is the central complex-assembly axis
atg101 — ATG101 joins the complex via ATG13 HORMA; ATG101 does not directly contact FIP200
p62 — FIP200 Claw domain directly binds the p62 FIR motif, coupling autophagy initiation to ubiquitin condensates ¹
atg16l1 — FIP200 recruits ATG16L1 to autophagosome precursors, distinguishing ULK1-complex-dependent from ULK1-independent LC3 conjugation ⁴
disabled-macroautophagy — hallmark page; FIP200 loss ablates autophagy initiation; aging-associated mTORC1 hyperactivity chronically suppresses ULK1 complex activity, at whose apex FIP200 sits
loss-of-proteostasis — FIP200-dependent selective autophagy clears ubiquitinated aggregates; loss impairs proteostasis maintenance in long-lived post-mitotic cells
alzheimers-disease, parkinsons-disease, neurodegeneration — neural Fip200 cKO phenocopies autophagy-deficient neurodegeneration; FIP200 is an upstream limiting factor in the proteostasis failure axis of brain aging

Key interactors

Interactor	Evidence type	Function
ulk1	Direct; co-IP; in vitro kinase	FIP200 stabilizes ULK1; stimulates ULK1 kinase activity; required for ULK1 localization to PAS ²
atg13	Direct; complex; co-IP	ATG13 bridges ULK1 to FIP200; the precise FIP200 domain mediating ATG13 contact is not established in papers cited here; FIP200 + ATG13 additively stimulate ULK1 ³ unsourced for Claw-ATG13 contact
atg101	Indirect; complex co-member	ATG101 joins via ATG13 HORMA–HORMA heterodimer; no direct FIP200–ATG101 binding reported
p62	Direct; Claw domain (aa 1494–1594); X-ray crystal structure + SPR	FIP200 Claw binds p62 FIR motif (aa 326–380); interaction enhanced by p62 phosphorylation; mutually exclusive with LC3B binding; directs ULK1 complex to ubiquitin condensates ¹
NDP52 (CALCOCO2)	Unverified — attribution to Turco 2019 is incorrect	Turco 2019 does not characterize FIP200–NDP52 binding. unsourced — requires primary source citation before this claim can be included
atg16l1	Direct; co-IP; functional	FIP200 recruits ATG16L1 to phagophore precursors ⁴
FAK/Pyk2	Direct (original discovery); co-IP	Original FIP200-interacting proteins (FAK family); role in autophagy context unclear — likely independent non-autophagic FIP200 functions; not detailed here unsourced

Limitations and knowledge gaps

Gap	Tag	Notes
No human FIP200 loss-of-function genetics	needs-human-replication	Germline KO is lethal in mouse; no human disease linked to FIP200 dysfunction
FIP200 expression changes with age	unsourced	Whether FIP200 protein levels or Claw-domain–mediated interactions decline in aged human tissue is unknown; inferred from general autophagy-decline literature
PTM landscape uncharacterized	unsourced	No regulatory phosphorylation/ubiquitination sites on FIP200 are established; PhosphoSitePlus cross-check needed
Claw–p62 interaction replication	needs-replication	p62 FIR binding to Claw (aa 1494–1594) characterized by Turco 2019 (two labs; X-ray crystallography + SPR + cell biology) — independent structural replication not yet published
NDP52 and ATG13 HORMA Claw contacts	unsourced	Claims that FIP200 Claw binds NDP52 CLIR motif and ATG13 HORMA were incorrectly attributed to Turco 2019; actual primary sources for these claims are unknown — removed pending proper citation
FIP200–ATG16L1 interface structure	needs-replication	Functional interaction and FBD (residues 229–242) confirmed (Gammoh 2013); no atomic-resolution structure of the FIP200–ATG16L1 interface available
Selective vs bulk autophagy contribution	no-mechanism	How much of FIP200’s aging-relevant function is selective (via Claw-cargo-receptor axis) vs bulk autophagy initiation is unknown
Tissue-specific cKO aging phenotypes	unsourced	Liver, heart, and skeletal muscle Fip200 cKO phenotypes not cited to primary sources in this page; requires follow-up citations
GenAge canonical ID	needs-canonical-id	FIP200/RB1CC1 not found in GenAge human subset as of 2026-05-04

Footnotes

turco-2019-fip200-claw-p62-condensates · doi:10.1016/j.molcel.2019.01.035 · n=N/A (structural + cell-based) · in-vitro · model: X-ray crystallography of FIP200 CTR (aa 1458–1594, 2.5–3.2 Å) and isolated Claw (aa 1494–1594, 1.56 Å); biochemical pull-downs in HeLa and HAP1 cells; SPR binding assays; two independent labs (Daumke/MDC Berlin + Martens/Univ. Vienna); key findings: FIP200 Claw domain (aa 1494–1594) directly binds p62 FIR motif (aa 326–380) via positively charged pocket; p62 phosphorylation at S365/S366/S370 enhances binding ~2-fold; FIP200–p62 binding mutually exclusive with LC3B binding to p62; FIP200 Claw deletion (FIP200ΔClaw) accumulates p62-ubiquitin condensates and impairs their autophagic clearance in HeLa cells. Corrections vs. prior draft: no cryo-EM performed; NDP52/CLIR binding not characterized in this paper; ATG13 HORMA–Claw interaction not characterized in this paper; Claw residues are 1494–1594, not 1485–1591 · 342 citations (FWCI 34.94, 100th percentile) · locally downloaded at ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸
hara-2008-fip200-ulk1-complex · doi:10.1083/jcb.200712064 · n=N/A (biochemical + cell-based) · in-vitro · model: FIP200-/- MEFs (from Gan et al. 2006 KO) and NIH3T3/HEK293T cells; key findings: FIP200 identified as ULK1/ULK2 binding partner (C-terminal region aa 829–1051 of ULK1 required); FIP200 required for ULK1 protein stability (faster cycloheximide turnover in FIP200-/- cells); FIP200 required for starvation-induced autophagosome formation and ULK1 puncta localization to isolation membrane; autophagy block in FIP200-/- MEFs is downstream of mTOR (rapamycin cannot rescue); FIP200 is dispensable for FAK-dependent autophagy regulation. Note: neural Fip200 cKO (Nestin-Cre) neurodegeneration phenotype is from Komatsu et al. 2006 (Nature 441:880), not this paper. Additive ULK1 kinase stimulation by FIP200+ATG13 is from Ganley et al. 2009, not this paper. · 963 citations (FWCI 34.24, 100th percentile) · locally downloaded at ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷
ganley-2009-ulk1-atg13-fip200-essential · doi:10.1074/jbc.m900573200 · n=N/A (biochemical + cell-based) · in-vitro · model: MEF (stable FLAG/S-ULK1 lines) and HEK293T cells · key findings: ULK1·ATG13·FIP200 trimeric complex essential for starvation-induced autophagy; FIP200 and ATG13 individually and additively stimulate ULK1 kinase activity in vitro; mTOR directly phosphorylates ULK1 and ATG13; ATG13 interacts with ULK1 independently of FIP200 and vice versa; ATG101 not described in this paper · 1,512 citations (FWCI 42.69, 100th percentile) · verified against local PDF at ↩ ↩² ↩³ ↩⁴
gammoh-2012-fip200-atg16l1-ulk1-dependent-autophagy · doi:10.1038/nsmb.2475 · Published Nat Struct Mol Biol 2013 Feb; 20(2):144–149 (file named “gammoh-2012” by seeder — year in filename is incorrect) · n=N/A (biochemical + cell-based) · in-vitro · model: 293T cells + ATG3-/- and ATG16L1-/- MEFs; key findings: FIP200 directly interacts with ATG16L1 independently of ATG5 and ATG13 (recombinant pull-down confirmed); the FIP200-binding domain (FBD) of ATG16L1 is residues 229–242; FBD deletion (ATG16L1ΔFBD) specifically blocks amino acid starvation-induced (ULK1-complex-dependent) autophagy while glucose deprivation-induced (ULK1-complex-independent) autophagy remains intact · 206 citations (FWCI 8.43) · locally downloaded at · DOI correction: task brief cited 10.1038/nsmb.2421 — correct DOI confirmed via PMID 23262492 as 10.1038/nsmb.2475 · needs-replication (single study; FIP200–ATG16L1 binding interface not yet independently resolved at atomic resolution) ↩ ↩² ↩³
gan-2006-fip200-ko-cardiac-liver · doi:10.1083/jcb.200604129 · n=N/A (germline mouse KO) · in-vivo · model: Fip200-/- (Rb1cc1-/-) mouse (background not stated explicitly in paper text); key findings: Fip200-null mice die between E13.5 and E16.5 (~25% dead at E14.5, ~60% at E15.5, none alive at E16.5; Table I); cardiac failure (ventricular dilation, sparse trabecular myocardium) and liver degeneration (disrupted architecture, multifocal hemorrhages); increased apoptosis in heart and liver at E14.5–E15.5; FIP200 KO MEFs show increased susceptibility to TNFα-induced apoptosis mediated by reduced JNK signaling; FIP200 deletion leads to increased TSC function and reduced S6K activation/cell size · 228 citations · locally downloaded at · DOI correction: task brief cited 10.1083/jcb.200603081 — corrected to 10.1083/jcb.200604129 via PubMed PMID lookup (efetch PMID 17015619) ↩

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