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Malleable machines in transcription regulation: the mediator complex.

Tóth-Petróczy A, Oldfield CJ, Simon I, Takagi Y, Dunker AK, Uversky VN, Fuxreiter M - PLoS Comput. Biol. (2008)

Bottom Line: Indeed, a high prevalence of IDRs was found in various subunits of Mediator from both Saccharomyces cerevisiae and Homo sapiens, especially in the Tail and the Middle modules.The level of disorder increases from yeast to man, although in both organisms it significantly exceeds that of multiprotein complexes of a similar size.All of these data suggest an integral role for intrinsic disorder in Mediator's function.

View Article: PubMed Central - PubMed

Affiliation: Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary.

ABSTRACT
The Mediator complex provides an interface between gene-specific regulatory proteins and the general transcription machinery including RNA polymerase II (RNAP II). The complex has a modular architecture (Head, Middle, and Tail) and cryoelectron microscopy analysis suggested that it undergoes dramatic conformational changes upon interactions with activators and RNAP II. These rearrangements have been proposed to play a role in the assembly of the preinitiation complex and also to contribute to the regulatory mechanism of Mediator. In analogy to many regulatory and transcriptional proteins, we reasoned that Mediator might also utilize intrinsically disordered regions (IDRs) to facilitate structural transitions and transmit transcriptional signals. Indeed, a high prevalence of IDRs was found in various subunits of Mediator from both Saccharomyces cerevisiae and Homo sapiens, especially in the Tail and the Middle modules. The level of disorder increases from yeast to man, although in both organisms it significantly exceeds that of multiprotein complexes of a similar size. IDRs can contribute to Mediator's function in three different ways: they can individually serve as target sites for multiple partners having distinctive structures; they can act as malleable linkers connecting globular domains that impart modular functionality on the complex; and they can also facilitate assembly and disassembly of complexes in response to regulatory signals. Short segments of IDRs, termed molecular recognition features (MoRFs) distinguished by a high protein-protein interaction propensity, were identified in 16 and 19 subunits of the yeast and human Mediator, respectively. In Saccharomyces cerevisiae, the functional roles of 11 MoRFs have been experimentally verified, and those in the Med8/Med18/Med20 and Med7/Med21 complexes were structurally confirmed. Although the Saccharomyces cerevisiae and Homo sapiens Mediator sequences are only weakly conserved, the arrangements of the disordered regions and their embedded interaction sites are quite similar in the two organisms. All of these data suggest an integral role for intrinsic disorder in Mediator's function.

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Schematic representation of the Mediator complex: Head (orange), Middle (green), Tail (yellow), CDK (blue).Subunits with higher than 50% average overall disorder (Med2, Med3 in Tail; Med9, Med19, Med26 in Middle and Med8 in Head) or subunits containing intrinsically disordered regions longer than 100 residues (Med12, Med13 of the CDK, Med1, Med9, Med26 of the Middle and Med15 of the Tail) in either Saccharomyces cerevisiae or in Homo sapiens are displayed by darker colors. Med19 and Med26 was assigned to the Middle module according to reference [80].
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pcbi-1000243-g005: Schematic representation of the Mediator complex: Head (orange), Middle (green), Tail (yellow), CDK (blue).Subunits with higher than 50% average overall disorder (Med2, Med3 in Tail; Med9, Med19, Med26 in Middle and Med8 in Head) or subunits containing intrinsically disordered regions longer than 100 residues (Med12, Med13 of the CDK, Med1, Med9, Med26 of the Middle and Med15 of the Tail) in either Saccharomyces cerevisiae or in Homo sapiens are displayed by darker colors. Med19 and Med26 was assigned to the Middle module according to reference [80].

Mentions: Intrinsically disordered regions of any length have been observed to be involved in biological functions, but those of 30 residues or longer have been especially well studied [36]. The function of these regions are diverse but are frequently related to molecular recognition [37]. IDRs are usually exploited for regulatory purposes as 66±5% of cell-signaling proteins [38], and 90% of transcription factors were predicted to contain IDRs (longer than 30 aa) [39],[40]. In Saccharomyces cerevisiae 80% of Mediator subunits have predicted IDRs equal to or longer than 30 residues, and 24% have IDRs above 100 residues in length [25] (Figure S3). In Homo sapiens, IDRs longer than 30 and 100 residues appear in 75% and 32% of Mediator proteins, respectively (Figure S3). This suggests that the length of IDRs increased from yeast to man. The number of disordered segments is also higher in the human complex than in the yeast complex (Figure 4). This is mostly due to the discrepancy in the number of IDRs in the Middle. This module is the most abundant in disordered regions in Homo sapiens. In the Head the propensity of IDRs is also slightly higher (below 70 residues in length) in man than in yeast. In Saccharomyces cerevisiae, disordered regions are preferably located in the Tail, some exceeding 100 residues in length. Along these lines, the longest IDRs in yeast are found in Med2 (334), Med3 (256), Med15 (263) of the Tail, whereas in human Mediator, Med1 (645), Med9 (241), Med26 (261) of the Middle are equipped with the longest IDRs (Figure 5 and Table S2). Med13 of the CDK appears to have a long IDR in both organisms: 226 and 162 in yeast and human, respectively.


Malleable machines in transcription regulation: the mediator complex.

Tóth-Petróczy A, Oldfield CJ, Simon I, Takagi Y, Dunker AK, Uversky VN, Fuxreiter M - PLoS Comput. Biol. (2008)

Schematic representation of the Mediator complex: Head (orange), Middle (green), Tail (yellow), CDK (blue).Subunits with higher than 50% average overall disorder (Med2, Med3 in Tail; Med9, Med19, Med26 in Middle and Med8 in Head) or subunits containing intrinsically disordered regions longer than 100 residues (Med12, Med13 of the CDK, Med1, Med9, Med26 of the Middle and Med15 of the Tail) in either Saccharomyces cerevisiae or in Homo sapiens are displayed by darker colors. Med19 and Med26 was assigned to the Middle module according to reference [80].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2588115&req=5

pcbi-1000243-g005: Schematic representation of the Mediator complex: Head (orange), Middle (green), Tail (yellow), CDK (blue).Subunits with higher than 50% average overall disorder (Med2, Med3 in Tail; Med9, Med19, Med26 in Middle and Med8 in Head) or subunits containing intrinsically disordered regions longer than 100 residues (Med12, Med13 of the CDK, Med1, Med9, Med26 of the Middle and Med15 of the Tail) in either Saccharomyces cerevisiae or in Homo sapiens are displayed by darker colors. Med19 and Med26 was assigned to the Middle module according to reference [80].
Mentions: Intrinsically disordered regions of any length have been observed to be involved in biological functions, but those of 30 residues or longer have been especially well studied [36]. The function of these regions are diverse but are frequently related to molecular recognition [37]. IDRs are usually exploited for regulatory purposes as 66±5% of cell-signaling proteins [38], and 90% of transcription factors were predicted to contain IDRs (longer than 30 aa) [39],[40]. In Saccharomyces cerevisiae 80% of Mediator subunits have predicted IDRs equal to or longer than 30 residues, and 24% have IDRs above 100 residues in length [25] (Figure S3). In Homo sapiens, IDRs longer than 30 and 100 residues appear in 75% and 32% of Mediator proteins, respectively (Figure S3). This suggests that the length of IDRs increased from yeast to man. The number of disordered segments is also higher in the human complex than in the yeast complex (Figure 4). This is mostly due to the discrepancy in the number of IDRs in the Middle. This module is the most abundant in disordered regions in Homo sapiens. In the Head the propensity of IDRs is also slightly higher (below 70 residues in length) in man than in yeast. In Saccharomyces cerevisiae, disordered regions are preferably located in the Tail, some exceeding 100 residues in length. Along these lines, the longest IDRs in yeast are found in Med2 (334), Med3 (256), Med15 (263) of the Tail, whereas in human Mediator, Med1 (645), Med9 (241), Med26 (261) of the Middle are equipped with the longest IDRs (Figure 5 and Table S2). Med13 of the CDK appears to have a long IDR in both organisms: 226 and 162 in yeast and human, respectively.

Bottom Line: Indeed, a high prevalence of IDRs was found in various subunits of Mediator from both Saccharomyces cerevisiae and Homo sapiens, especially in the Tail and the Middle modules.The level of disorder increases from yeast to man, although in both organisms it significantly exceeds that of multiprotein complexes of a similar size.All of these data suggest an integral role for intrinsic disorder in Mediator's function.

View Article: PubMed Central - PubMed

Affiliation: Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary.

ABSTRACT
The Mediator complex provides an interface between gene-specific regulatory proteins and the general transcription machinery including RNA polymerase II (RNAP II). The complex has a modular architecture (Head, Middle, and Tail) and cryoelectron microscopy analysis suggested that it undergoes dramatic conformational changes upon interactions with activators and RNAP II. These rearrangements have been proposed to play a role in the assembly of the preinitiation complex and also to contribute to the regulatory mechanism of Mediator. In analogy to many regulatory and transcriptional proteins, we reasoned that Mediator might also utilize intrinsically disordered regions (IDRs) to facilitate structural transitions and transmit transcriptional signals. Indeed, a high prevalence of IDRs was found in various subunits of Mediator from both Saccharomyces cerevisiae and Homo sapiens, especially in the Tail and the Middle modules. The level of disorder increases from yeast to man, although in both organisms it significantly exceeds that of multiprotein complexes of a similar size. IDRs can contribute to Mediator's function in three different ways: they can individually serve as target sites for multiple partners having distinctive structures; they can act as malleable linkers connecting globular domains that impart modular functionality on the complex; and they can also facilitate assembly and disassembly of complexes in response to regulatory signals. Short segments of IDRs, termed molecular recognition features (MoRFs) distinguished by a high protein-protein interaction propensity, were identified in 16 and 19 subunits of the yeast and human Mediator, respectively. In Saccharomyces cerevisiae, the functional roles of 11 MoRFs have been experimentally verified, and those in the Med8/Med18/Med20 and Med7/Med21 complexes were structurally confirmed. Although the Saccharomyces cerevisiae and Homo sapiens Mediator sequences are only weakly conserved, the arrangements of the disordered regions and their embedded interaction sites are quite similar in the two organisms. All of these data suggest an integral role for intrinsic disorder in Mediator's function.

Show MeSH