Dimerization Mediated by a Divergent Forkhead-associated Domain Is Essential for the DNA Damage and Spindle Functions of Fission Yeast Mdb1

Luo, Shukun; Xin, Xiaoran; Du, Li-Lin; Ye, Keqiong; Yi, Wei

doi:10.1074/jbc.m115.642538

Cited by 10 publications

(10 citation statements)

References 42 publications

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“…This internal deletion disrupted the self-interaction of Atg11 To determine whether mediating homodimerization is the only function of the C terminal part of Atg11(522-583), we tested whether this part can be replaced by a heterologous dimerization domain. We fused a 32-amino-acid-long homodimerizing leucine zipper motif (LZ) (Luo et al, 2015) to Atg11 fragments, and examined the ability of the fusion proteins to complement the autophagy phenotype of atg11Δ. LZ fusion fully restored the ability of Atg11(522-552) to complement atg11Δ ( Figures 3F and 3G).…”

Section: Atg11(546-583) Mediates Homodimerizationmentioning

confidence: 99%

Atg1 kinase in fission yeast is activated by Atg11-mediated dimerization and cis-autophosphorylation

Pan

Shao

Liu

et al. 2020

eLife

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Autophagy is a proteolytic pathway conserved from yeasts to mammals. Atg1 kinase is essential for autophagy but how its activity is controlled remains insufficiently understood. Here, we show that, in the fission yeast Schizosaccharomyces pombe, Atg1 kinase activity requires Atg11, the ortholog of mammalian FIP200/RB1CC1, but does not require Atg13, Atg17, or Atg101. Remarkably, a 62-amino-acid region of Atg11 is sufficient for the autophagy function of Atg11 and for supporting the Atg1 kinase activity. This region harbors an Atg1-binding domain and a homodimerization domain. Dimerizing Atg1 is the main role of Atg11, as it can be bypassed by artificially dimerizing Atg1. In an Atg1 dimer, only one Atg1 molecule needs to be catalytically active, suggesting that Atg1 activation can be achieved through cis-autophosphorylation. We propose that mediating Atg1 oligomerization and activation may be a conserved function of Atg11/FIP200 family proteins and cis-autophosphorylation may be a general mechanism of Atg1 activation.

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Section: Atg11(546-583) Mediates Homodimerizationmentioning

confidence: 99%

Atg1 kinase in fission yeast is activated by Atg11-mediated dimerization and cis-autophosphorylation

Pan

Shao

Liu

et al. 2020

eLife

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“…It was generally believed that FHA domains recognize unstructured sequences containing a phosphorylated amino acid –often a threonine. Recent studies, however, have shown that FHA domains can also use alternate surfaces for protein oligomerization and to mediate protein-protein interactions 15 16 17 18 19 . The Dbf4-dependent kinase (DDK) and Rad9 are two binding partners of Rad53 during the replication checkpoint response.…”

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confidence: 99%

‘AND’ logic gates at work: Crystal structure of Rad53 bound to Dbf4 and Cdc7

Almawi¹,

Matthews²,

Larasati

et al. 2016

Sci Rep

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Forkhead-associated (FHA) domains are phosphopeptide recognition modules found in many signaling proteins. The Saccharomyces cerevisiae protein kinase Rad53 is a key regulator of the DNA damage checkpoint and uses its two FHA domains to interact with multiple binding partners during the checkpoint response. One of these binding partners is the Dbf4-dependent kinase (DDK), a heterodimer composed of the Cdc7 kinase and its regulatory subunit Dbf4. Binding of Rad53 to DDK, through its N-terminal FHA (FHA1) domain, ultimately inhibits DDK kinase activity, thereby preventing firing of late origins. We have previously found that the FHA1 domain of Rad53 binds simultaneously to Dbf4 and a phosphoepitope, suggesting that this domain functions as an ‘AND’ logic gate. Here, we present the crystal structures of the FHA1 domain of Rad53 bound to Dbf4, in the presence and absence of a Cdc7 phosphorylated peptide. Our results reveal how the FHA1 uses a canonical binding interface to recognize the Cdc7 phosphopeptide and a non-canonical interface to bind Dbf4. Based on these data we propose a mechanism to explain how Rad53 enhances the specificity of FHA1-mediated transient interactions.

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“…Forkhead-associated (FHA) domain was first discovered in 1995 and later recognized for its unique structural feature , and specificity for binding phosphothreonine (pThr). − This protein–phosphoprotein interaction motif is conserved in prokaryotes and eukaryotes . However, the flanking residues are much more diverse, , and phosphorylation-independent interactions have also been reported. , In contrast to its highly conserved β-sandwich architecture, which is composed of a five-stranded β-sheet and a six-stranded β-sheet, the loops connecting β-strands vary in length. Furthermore, FHA domains overall have a relatively low level of sequence homology.…”

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confidence: 99%

Uncovering the Mechanism of Forkhead-Associated Domain-Mediated TIFA Oligomerization That Plays a Central Role in Immune Responses

et al. 2015

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Forkhead-associated (FHA) domain is the only signaling domain that recognizes phosphothreonine (pThr) specifically. TRAF-interacting protein with an FHA domain (TIFA) was shown to be involved in immune responses by binding with TRAF2 and TRAF6. We recently reported that TIFA is a dimer in solution and that, upon stimulation by TNF-α, TIFA is phosphorylated at Thr9, which triggers TIFA oligomerization via pThr9-FHA domain binding and activates nuclear factor κB (NF-κB). However, the structural mechanism for the functionally important TIFA oligomerization remains to be established. While FHA domain-pThr binding is known to mediate protein dimerization, its role in oligomerization has not been demonstrated at the structural level. Here we report the crystal structures of TIFA (residues 1-150, with the unstructured C-terminal tail truncated) and its complex with the N-terminal pThr9 peptide (residues 1-15), which show unique features in the FHA structure (intrinsic dimer and extra β-strand) and in its interaction with the pThr peptide (with residues preceding rather than following pThr). These structural features support previous and additional functional analyses. Furthermore, the structure of the complex suggests that the pThr9-FHA domain interaction can occur only between different sets of dimers rather than between the two protomers within a dimer, providing the structural mechanism for TIFA oligomerization. Our results uncover the mechanism of FHA domain-mediated oligomerization in a key step of immune responses and expand the paradigm of FHA domain structure and function.

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Dimerization Mediated by a Divergent Forkhead-associated Domain Is Essential for the DNA Damage and Spindle Functions of Fission Yeast Mdb1

Cited by 10 publications

References 42 publications

Atg1 kinase in fission yeast is activated by Atg11-mediated dimerization and cis-autophosphorylation

Atg1 kinase in fission yeast is activated by Atg11-mediated dimerization and cis-autophosphorylation

‘AND’ logic gates at work: Crystal structure of Rad53 bound to Dbf4 and Cdc7

Uncovering the Mechanism of Forkhead-Associated Domain-Mediated TIFA Oligomerization That Plays a Central Role in Immune Responses

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