Protein folding (Homo sapiens)

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Bibliography

1. Plimpton RL, Cuéllar J, Lai CW, Aoba T, Makaju A, Franklin S, Mathis AD, Prince JT, Carrascosa JL, Valpuesta JM, Willardson BM.; ''Structures of the Gβ-CCT and PhLP1-Gβ-CCT complexes reveal a mechanism for G-protein β-subunit folding and Gβγ dimer assembly.''; PubMed Europe PMC Scholia
2. Freund A, Zhong FL, Venteicher AS, Meng Z, Veenstra TD, Frydman J, Artandi SE.; ''Proteostatic control of telomerase function through TRiC-mediated folding of TCAB1.''; PubMed Europe PMC Scholia
3. Litterman N, Ikeuchi Y, Gallardo G, O'Connell BC, Sowa ME, Gygi SP, Harper JW, Bonni A.; ''An OBSL1-Cul7Fbxw8 ubiquitin ligase signaling mechanism regulates Golgi morphology and dendrite patterning.''; PubMed Europe PMC Scholia
4. Kubota H, Hynes GM, Kerr SM, Willison KR.; ''Tissue-specific subunit of the mouse cytosolic chaperonin-containing TCP-1.''; PubMed Europe PMC Scholia
5. Naletova IN, Popova KM, Eldarov MA, Kuravsky ML, Schmalhausen EV, Sevostyanova IA, Muronetz VI.; ''Chaperonin TRiC assists the refolding of sperm-specific glyceraldehyde-3-phosphate dehydrogenase.''; PubMed Europe PMC Scholia
6. Lukov GL, Baker CM, Ludtke PJ, Hu T, Carter MD, Hackett RA, Thulin CD, Willardson BM.; ''Mechanism of assembly of G protein betagamma subunits by protein kinase CK2-phosphorylated phosducin-like protein and the cytosolic chaperonin complex.''; PubMed Europe PMC Scholia
7. Bigotti MG, Clarke AR.; ''Chaperonins: The hunt for the Group II mechanism.''; PubMed Europe PMC Scholia
8. Tian G, Lewis SA, Feierbach B, Stearns T, Rommelaere H, Ampe C, Cowan NJ.; ''Tubulin subunits exist in an activated conformational state generated and maintained by protein cofactors.''; PubMed Europe PMC Scholia
9. Lu J, Chiang J, Iyer RR, Thompson E, Kaneski CR, Xu DS, Yang C, Chen M, Hodes RJ, Lonser RR, Brady RO, Zhuang Z.; ''Decreased glucocerebrosidase activity in Gaucher disease parallels quantitative enzyme loss due to abnormal interaction with TCP1 and c-Cbl.''; PubMed Europe PMC Scholia
10. Young JC, Agashe VR, Siegers K, Hartl FU.; ''Pathways of chaperone-mediated protein folding in the cytosol.''; PubMed Europe PMC Scholia
11. Yam AY, Xia Y, Lin HT, Burlingame A, Gerstein M, Frydman J.; ''Defining the TRiC/CCT interactome links chaperonin function to stabilization of newly made proteins with complex topologies.''; PubMed Europe PMC Scholia
12. Won KA, Schumacher RJ, Farr GW, Horwich AL, Reed SI.; ''Maturation of human cyclin E requires the function of eukaryotic chaperonin CCT.''; PubMed Europe PMC Scholia
13. Bhamidipati A, Lewis SA, Cowan NJ.; ''ADP ribosylation factor-like protein 2 (Arl2) regulates the interaction of tubulin-folding cofactor D with native tubulin.''; PubMed Europe PMC Scholia
14. Lai CW, Kolesnikov AV, Frederick JM, Blake DR, Jiang L, Stewart JS, Chen CK, Barrow JR, Baehr W, Kefalov VJ, Willardson BM.; ''Phosducin-like protein 1 is essential for G-protein assembly and signaling in retinal rod photoreceptors.''; PubMed Europe PMC Scholia
15. Lukov GL, Hu T, McLaughlin JN, Hamm HE, Willardson BM.; ''Phosducin-like protein acts as a molecular chaperone for G protein betagamma dimer assembly.''; PubMed Europe PMC Scholia
16. Tracy CM, Kolesnikov AV, Blake DR, Chen CK, Baehr W, Kefalov VJ, Willardson BM.; ''Retinal cone photoreceptors require phosducin-like protein 1 for G protein complex assembly and signaling.''; PubMed Europe PMC Scholia
17. Guenther MG, Yu J, Kao GD, Yen TJ, Lazar MA.; ''Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex.''; PubMed Europe PMC Scholia
18. Howlett AC, Gray AJ, Hunter JM, Willardson BM.; ''Role of molecular chaperones in G protein beta5/regulator of G protein signaling dimer assembly and G protein betagamma dimer specificity.''; PubMed Europe PMC Scholia
19. Wells CA, Dingus J, Hildebrandt JD.; ''Role of the chaperonin CCT/TRiC complex in G protein betagamma-dimer assembly.''; PubMed Europe PMC Scholia
20. Melki R, Batelier G, Soulié S, Williams RC.; ''Cytoplasmic chaperonin containing TCP-1: structural and functional characterization.''; PubMed Europe PMC Scholia
21. Miyata Y, Shibata T, Aoshima M, Tsubata T, Nishida E.; ''The molecular chaperone TRiC/CCT binds to the Trp-Asp 40 (WD40) repeat protein WDR68 and promotes its folding, protein kinase DYRK1A binding, and nuclear accumulation.''; PubMed Europe PMC Scholia
22. Tian G, Thomas S, Cowan NJ.; ''Effect of TBCD and its regulatory interactor Arl2 on tubulin and microtubule integrity.''; PubMed Europe PMC Scholia
23. Zebol JR, Hewitt NM, Moretti PA, Lynn HE, Lake JA, Li P, Vadas MA, Wattenberg BW, Pitson SM.; ''The CCT/TRiC chaperonin is required for maturation of sphingosine kinase 1.''; PubMed Europe PMC Scholia
24. Spiess C, Meyer AS, Reissmann S, Frydman J.; ''Mechanism of the eukaryotic chaperonin: protein folding in the chamber of secrets.''; PubMed Europe PMC Scholia
25. Trinidad AG, Muller PA, Cuellar J, Klejnot M, Nobis M, Valpuesta JM, Vousden KH.; ''Interaction of p53 with the CCT complex promotes protein folding and wild-type p53 activity.''; PubMed Europe PMC Scholia
26. Kasembeli M, Lau WC, Roh SH, Eckols TK, Frydman J, Chiu W, Tweardy DJ.; ''Modulation of STAT3 folding and function by TRiC/CCT chaperonin.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
ACTB(1-375)	Protein	P60709 (Uniprot-TrEMBL)
ADP	Metabolite	CHEBI:16761 (ChEBI)
ADP	Metabolite	CHEBI:16761 (ChEBI)
ARL2	Protein	P36404 (Uniprot-TrEMBL)
ATP	Metabolite	CHEBI:15422 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
CCT/TriC (ADP) associated actin	Complex	R-HSA-390476 (Reactome)
CCT/TriC substrate proteins with unknown chaperones		R-HSA-390473 (Reactome)
CCT/TriC(ADP)-associated non-native tubulin	Complex	R-HSA-390501 (Reactome)
CCT/TriC(ADP):Sphingosine kinase 1	Complex	R-HSA-391256 (Reactome)
CCT/TriC(ADP)	Complex	R-HSA-390455 (Reactome)
CCT/TriC(ATP)-associated actin	Complex	R-HSA-390499 (Reactome)
CCT/TriC(ATP):unfolded tubulin complex	Complex	R-HSA-390446 (Reactome)
CCT/TriC:substrate complex	Complex	R-HSA-390481 (Reactome)
CCT2	Protein	P78371 (Uniprot-TrEMBL)
CCT3	Protein	P49368 (Uniprot-TrEMBL)
CCT4	Protein	P50991 (Uniprot-TrEMBL)
CCT5	Protein	P48643 (Uniprot-TrEMBL)
CCT6A	Protein	P40227 (Uniprot-TrEMBL)
CCT7	Protein	Q99832 (Uniprot-TrEMBL)
CCT8	Protein	P50990 (Uniprot-TrEMBL)
Cofactor B:GTP-alpha tubulin	Complex	R-HSA-391241 (Reactome)
Cofactor D:GTP:beta tubulin	Complex	R-HSA-391245 (Reactome)
Cofactor E:GTP-alpha tubulin folding	Complex	R-HSA-391242 (Reactome)
GTP	Metabolite	CHEBI:15996 (ChEBI)
GTP-alpha-tubulin folding intermediate	Complex	R-HSA-391235 (Reactome)
GTP:beta-tubulin folding intermediate	Complex	R-HSA-391246 (Reactome)
GTP	Metabolite	CHEBI:15996 (ChEBI)
PFDN1	Protein	O60925 (Uniprot-TrEMBL)
PFDN2	Protein	Q9UHV9 (Uniprot-TrEMBL)
PFDN4	Protein	Q9NQP4 (Uniprot-TrEMBL)
PFDN5	Protein	Q99471 (Uniprot-TrEMBL)
PFDN6	Protein	O15212 (Uniprot-TrEMBL)
Pi	Metabolite	CHEBI:18367 (ChEBI)
Prefoldin-associated actin/tubulin	Complex	R-HSA-390460 (Reactome)
Prefoldin	Complex	R-HSA-390452 (Reactome)
SPHK1	Protein	Q9NYA1 (Uniprot-TrEMBL)
SPHK1	Protein	Q9NYA1 (Uniprot-TrEMBL)
TBCA	Protein	O75347 (Uniprot-TrEMBL)
TBCA	Protein	O75347 (Uniprot-TrEMBL)
TBCB	Protein	Q99426 (Uniprot-TrEMBL)
TBCB	Protein	Q99426 (Uniprot-TrEMBL)
TBCC	Protein	Q15814 (Uniprot-TrEMBL)
TBCC	Protein	Q15814 (Uniprot-TrEMBL)
TBCD	Protein	Q9BTW9 (Uniprot-TrEMBL)
TBCD	Protein	Q9BTW9 (Uniprot-TrEMBL)
TBCE	Protein	Q15813 (Uniprot-TrEMBL)
TBCE	Protein	Q15813 (Uniprot-TrEMBL)
TCP1	Protein	P17987 (Uniprot-TrEMBL)
TUBA1A folding intermediate	Protein	Q71U36 (Uniprot-TrEMBL)
TUBA1A unfolded	Protein	Q71U36 (Uniprot-TrEMBL)
TUBA1B folding intermediate	Protein	P68363 (Uniprot-TrEMBL)
TUBA1B unfolded	Protein	P68363 (Uniprot-TrEMBL)
TUBA1C folding intermediate	Protein	Q9BQE3 (Uniprot-TrEMBL)
TUBA1C unfolded	Protein	Q9BQE3 (Uniprot-TrEMBL)
TUBA3C folding intermediate	Protein	Q13748 (Uniprot-TrEMBL)
TUBA3C unfolded	Protein	Q13748 (Uniprot-TrEMBL)
TUBA4A folding intermediate	Protein	P68366 (Uniprot-TrEMBL)
TUBA4A unfolded	Protein	P68366 (Uniprot-TrEMBL)
TUBB1	Protein	Q9H4B7 (Uniprot-TrEMBL)
TUBB1 folding intermediate	Protein	Q9H4B7 (Uniprot-TrEMBL)
TUBB1 unfolded	Protein	Q9H4B7 (Uniprot-TrEMBL)
TUBB2A	Protein	Q13885 (Uniprot-TrEMBL)
TUBB2A folding intermediate	Protein	Q13885 (Uniprot-TrEMBL)
TUBB2A unfolded	Protein	Q13885 (Uniprot-TrEMBL)
TUBB2B	Protein	Q9BVA1 (Uniprot-TrEMBL)
TUBB2B folding intermediate	Protein	Q9BVA1 (Uniprot-TrEMBL)
TUBB2B unfolded	Protein	Q9BVA1 (Uniprot-TrEMBL)
TUBB3	Protein	Q13509 (Uniprot-TrEMBL)
TUBB3 folding intermediate	Protein	Q13509 (Uniprot-TrEMBL)
TUBB3 unfolded	Protein	Q13509 (Uniprot-TrEMBL)
TUBB4A	Protein	P04350 (Uniprot-TrEMBL)
TUBB4A folding intermediate	Protein	P04350 (Uniprot-TrEMBL)
TUBB4A unfolded	Protein	P04350 (Uniprot-TrEMBL)
TUBB4B	Protein	P68371 (Uniprot-TrEMBL)
TUBB4B folding intermediate	Protein	P68371 (Uniprot-TrEMBL)
TUBB4B unfolded	Protein	P68371 (Uniprot-TrEMBL)
TUBB6	Protein	Q9BUF5 (Uniprot-TrEMBL)
TUBB6 folding intermediate	Protein	Q9BUF5 (Uniprot-TrEMBL)
TUBB6 unfolded	Protein	Q9BUF5 (Uniprot-TrEMBL)
Unfolded ACTB	Protein	P60709 (Uniprot-TrEMBL)
VBP1	Protein	P61758 (Uniprot-TrEMBL)
actin/tubulin-bound CCT/TriC(ADP)	Complex	R-HSA-390495 (Reactome)
alpha-beta heterodimer	Complex	R-HSA-391248 (Reactome)
beta tubulin:GTP: Cofactor D:alpha tubulin:GTP:Cofactor E	Complex	R-HSA-391236 (Reactome)
beta-tubulin:GTP:Cofactor D:alpha-tubulin:GTP:Cofactor E : Cofactor C	Complex	R-HSA-391240 (Reactome)
cofactor A:GTP:beta-tubulin folding intermediate	Complex	R-HSA-391239 (Reactome)
tubulin-GTP folding intermediate	Complex	R-HSA-390457 (Reactome)
unfolded actin/tubulin		R-HSA-390445 (Reactome)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	ACTB(1-375)	Arrow	R-HSA-390453 (Reactome)
	ADP	Arrow	R-HSA-389961 (Reactome)
	ADP	Arrow	R-HSA-390459 (Reactome)
ARL2		TBar	R-HSA-389969 (Reactome)
ATP			R-HSA-389961 (Reactome)
ATP			R-HSA-390459 (Reactome)
CCT/TriC (ADP) associated actin			R-HSA-390459 (Reactome)
CCT/TriC substrate proteins with unknown chaperones			R-HSA-390470 (Reactome)
CCT/TriC(ADP)-associated non-native tubulin			R-HSA-389961 (Reactome)
	CCT/TriC(ADP):Sphingosine kinase 1	Arrow	R-HSA-391266 (Reactome)
	CCT/TriC(ADP)	Arrow	R-HSA-389954 (Reactome)
	CCT/TriC(ADP)	Arrow	R-HSA-390453 (Reactome)
CCT/TriC(ADP)			R-HSA-389970 (Reactome)
CCT/TriC(ADP)			R-HSA-390470 (Reactome)
CCT/TriC(ADP)			R-HSA-391266 (Reactome)
	CCT/TriC(ATP)-associated actin	Arrow	R-HSA-390459 (Reactome)
CCT/TriC(ATP)-associated actin			R-HSA-390453 (Reactome)
	CCT/TriC(ATP):unfolded tubulin complex	Arrow	R-HSA-389961 (Reactome)
CCT/TriC(ATP):unfolded tubulin complex			R-HSA-389954 (Reactome)
	CCT/TriC:substrate complex	Arrow	R-HSA-390470 (Reactome)
	Cofactor B:GTP-alpha tubulin	Arrow	R-HSA-389972 (Reactome)
Cofactor B:GTP-alpha tubulin			R-HSA-389963 (Reactome)
	Cofactor D:GTP:beta tubulin	Arrow	R-HSA-389955 (Reactome)
	Cofactor D:GTP:beta tubulin	Arrow	R-HSA-389969 (Reactome)
Cofactor D:GTP:beta tubulin			R-HSA-389976 (Reactome)
	Cofactor E:GTP-alpha tubulin folding	Arrow	R-HSA-389963 (Reactome)
	Cofactor E:GTP-alpha tubulin folding	Arrow	R-HSA-389978 (Reactome)
Cofactor E:GTP-alpha tubulin folding			R-HSA-389976 (Reactome)
GTP-alpha-tubulin folding intermediate			R-HSA-389972 (Reactome)
GTP-alpha-tubulin folding intermediate			R-HSA-389978 (Reactome)
GTP:beta-tubulin folding intermediate			R-HSA-389956 (Reactome)
GTP:beta-tubulin folding intermediate			R-HSA-389969 (Reactome)
GTP			R-HSA-389954 (Reactome)
	Pi	Arrow	R-HSA-389954 (Reactome)
	Pi	Arrow	R-HSA-389974 (Reactome)
	Pi	Arrow	R-HSA-390453 (Reactome)
	Prefoldin-associated actin/tubulin	Arrow	R-HSA-389980 (Reactome)
Prefoldin-associated actin/tubulin			R-HSA-389970 (Reactome)
	Prefoldin	Arrow	R-HSA-389970 (Reactome)
Prefoldin			R-HSA-389980 (Reactome)
			R-HSA-389954 (Reactome)	Group II chaperonins enclose substrate proteins following substrate binding through the formation of a "built- in" lid over the central cavity. Upon ATP binding, lid formation is triggered by the transition state of ATP hydrolysis (Meyer, et al., 2003). In the case of CCT-mediated tubulin folding, one or more rounds of ATP hydrolysis are likely required before the association of non-exchangeable GTP with chaperonin-bound alpha tubulin.
			R-HSA-389955 (Reactome)	Factor A:beta tubulin complex act as a reservoir capable of accepting or delivering its target tubulin protein to cofactor D (Tian et al., 1997). In the reverse reaction, Cofactor A may displace cofactor D in a cofactor D:beta tubulin complex.
			R-HSA-389956 (Reactome)	Beta-tubulin folding intermediates generated via ATP-dependent interaction with TriC/CCT are captured by tubulin-specific chaperones A and D (TBCA and TBCD) (Tian et al. 1996, Tian et al. 1997) in a reversible reaction forming tubulin intermediate/cofactor complexes Factor A:beta tubulin or Factor D:beta tubulin. TBCD is involved in the tubulin-folding pathway, acting as a GTPase activating protein (GAP) for beta-tubulin. The ADP-ribosylation factor-like protein 2 (ARL2) is able to down-regulate TBCD specifically, thus preventing microtuble disruption (Bhamidipati et al. 2000, Tian et al. 2010).
			R-HSA-389961 (Reactome)	The interaction between CCT and unfolded target proteins is thought to occur when CCT is in its ADP-bound state. ADP is then exchanged for ATP in CCT.
			R-HSA-389963 (Reactome)	The factor B:alpha tubulin complex act as a reservoir capable of accepting or delivering alpha tubulin to cofactor E (Tian et al., 1997). In the reverse reaction, cofactor B may displace cofactor E in the cofactor E:alpha tubulin complex.
			R-HSA-389964 (Reactome)	Entry of cofactor C to the factor E:alpha tubulin: factor D:beta tubulin complex generates the active alpha:beta-supercomplex (Tian et al., 1997).
			R-HSA-389969 (Reactome)	Beta-tubulin folding intermediates generated via ATP-dependent interaction with TriC/CCT are captured by tubulin-specific chaperones A and D (TBCA and TBCD) (Tian et al. 1996, Tian et al. 1997) in a reversible reaction forming tubulin intermediate/cofactor complexes Factor A:beta tubulin or Factor D:beta tubulin. TBCD is involved in the tubulin-folding pathway, acting as a GTPase activating protein (GAP) for beta-tubulin. The ADP-ribosylation factor-like protein 2 (ARL2) is able to down-regulate TBCD specifically, thus preventing microtuble disruption (Bhamidipati et al. 2000, Tian et al. 2010).
			R-HSA-389970 (Reactome)	Unfolded actins and tubulins compete efficiently for binding to TriC/CCT and their chaperonin binding sites appear to be at least in part overlapping (Melki et al., 1993).
			R-HSA-389972 (Reactome)	Quasi-native alpha-tubulin folding intermediates generated via ATP-dependent interaction with CCT (Tian et al., 1995) are captured in a reversible reaction by cofactors B and/or E (Tian et al., 1997), forming the tubulin intermediate/cofactor complexes Factor B:alpha tubulin or Factor E:alpha tubulin.
			R-HSA-389974 (Reactome)	Beta tubulin within the active (Factor E:alpha tubulin: Factor D:beta tubulin:Factor C )-supercomplex hydrolyzes GTP. This results in the dissociation of the complex and the release of the native tubulin heterodimer (Tian et al., 1997).
			R-HSA-389976 (Reactome)	Factor E:alpha tubulin and Factor D:beta tubulin interact with each other in a reversible reaction to form the complex (Factor E alpha tubulin:Factor D:beta tubulin) (Tian et al., 1997).
			R-HSA-389978 (Reactome)	Quasi-native alpha-tubulin folding intermediates generated via ATP-dependent interaction with CCT (Tian et al., 1995) are captured in a reversible reaction by cofactors B and/or E (Tian et al., 1997), forming the tubulin intermediate/cofactor complexes Factor B:alpha tubulin or Factor E:alpha tubulin.
			R-HSA-389980 (Reactome)	During the synthesis of actin and tubulin, the nascent ribosome-associated chains bind to the heteromeric chaperone protein, prefoldin (PFD) (Hansen et al., 1999).
			R-HSA-390453 (Reactome)	TriC/CCT-mediated beta-actin folding involves rapid ATP-independent formation of a binary complex, followed by a slower ATP-dependent release of the native product (Gao et al., 1992). Group II chaperonins enclose substrate proteins following substrate binding through the formation of a "built- in" lid over the central cavity. Upon ATP binding, lid formation is triggered by the transition state of ATP hydrolysis (Meyer, et al., 2003).
			R-HSA-390459 (Reactome)	The interaction between CCT and unfolded target proteins is thought to occur when CCT is in its ADP-bound state. ADP is then exchanged for ATP in CCT.
			R-HSA-390470 (Reactome)	A combination of proteomic and bioinformatics analyses of TRiC substrates has revealed that they have complex topologies that are slow folding and aggregation prone (Yam et al., 2008). These substrates are also enriched in proteins that belong to oligomeric assemblies suggesting that TRiC plays a role in promoting complex assembly (Yam et al., 2008). Two possible mechanisms describing the role of TriC have been suggested (Yam et al., 2008). The processes of TRiC-mediated folding and assembly could be directly coupled, or TRiC could fold monomeric subunits and hold them in an assembly-competent state until they associate with the appropriate partner subunits. The complete list of TriC subsrates is not yet known. Many of its substrates that are targeted during biosynthesis are conserved between mammals and yeast (Yam et al. 2008).
			R-HSA-391266 (Reactome)	CCT/TRiC facilitates folding of newly translated SK1 into its mature active form (Zebol et al., 2008)
SPHK1			R-HSA-391266 (Reactome)
	TBCA	Arrow	R-HSA-389955 (Reactome)
TBCA			R-HSA-389956 (Reactome)
	TBCB	Arrow	R-HSA-389963 (Reactome)
TBCB			R-HSA-389972 (Reactome)
	TBCC	Arrow	R-HSA-389974 (Reactome)
TBCC			R-HSA-389964 (Reactome)
	TBCD	Arrow	R-HSA-389974 (Reactome)
TBCD			R-HSA-389955 (Reactome)
TBCD			R-HSA-389969 (Reactome)
	TBCE	Arrow	R-HSA-389974 (Reactome)
TBCE			R-HSA-389963 (Reactome)
TBCE			R-HSA-389978 (Reactome)
	actin/tubulin-bound CCT/TriC(ADP)	Arrow	R-HSA-389970 (Reactome)
	alpha-beta heterodimer	Arrow	R-HSA-389974 (Reactome)
	beta tubulin:GTP: Cofactor D:alpha tubulin:GTP:Cofactor E	Arrow	R-HSA-389976 (Reactome)
beta tubulin:GTP: Cofactor D:alpha tubulin:GTP:Cofactor E			R-HSA-389964 (Reactome)
	beta-tubulin:GTP:Cofactor D:alpha-tubulin:GTP:Cofactor E : Cofactor C	Arrow	R-HSA-389964 (Reactome)
beta-tubulin:GTP:Cofactor D:alpha-tubulin:GTP:Cofactor E : Cofactor C			R-HSA-389974 (Reactome)
	cofactor A:GTP:beta-tubulin folding intermediate	Arrow	R-HSA-389956 (Reactome)
cofactor A:GTP:beta-tubulin folding intermediate			R-HSA-389955 (Reactome)
	tubulin-GTP folding intermediate	Arrow	R-HSA-389954 (Reactome)
unfolded actin/tubulin			R-HSA-389980 (Reactome)