David Fushman

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Top‐down analysis of novel synthetic branched proteins

Fabio Gomes, Betsegaw Lemma, Dulith Abeykoon, Dapeng Chen, more

Journal of Mass Spectrometry > 54 > 1 > 19 - 25

A strategy for top‐down analysis of branched proteins has been reported earlier, which relies on electron transfer dissociation assisted by collisional activation, and software designed for graphic interpretation of tandem mass spectra and adapted for branched proteins. In the present study, the strategy is applied to identify unknown and novel products of reactions in which rationally mutated proteoforms...

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Autoinhibition in Ras effectors Raf, PI3Kα, and RASSF5: a comprehensive review underscoring the challenges in pharmacological intervention

Ruth Nussinov, Mingzhen Zhang, Chung-Jung Tsai, Tsung-Jen Liao, more

Biophysical Reviews > 2018 > 10 > 5 > 1263-1282

Autoinhibition is an effective mechanism that guards proteins against spurious activation. Despite its ubiquity, the distinct organizations of the autoinhibited states and their release mechanisms differ. Signaling is most responsive to the cell environment only if a small shift in the equilibrium is required to switch the system from an inactive (occluded) to an active (exposed) state. Ras signaling...

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Structural Basis for the Inhibitory Effects of Ubistatins in the Ubiquitin-Proteasome Pathway

Mark A. Nakasone, Timothy A. Lewis, Olivier Walker, Anita Thakur, more

Structure > 2017 > 25 > 12 > 1839-1855.e11

The discovery of ubistatins, small molecules that impair proteasomal degradation of proteins by directly binding to polyubiquitin, makes ubiquitin itself a potential therapeutic target. Although ubistatins have the potential for drug development and clinical applications, the lack of structural details of ubiquitin-ubistatin interactions has impeded their development. Here, we characterized a panel...

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Intrinsic protein disorder in oncogenic KRAS signaling

Ruth Nussinov, Hyunbum Jang, Chung-Jung Tsai, Tsung-Jen Liao, more

Cellular and Molecular Life Sciences > 2017 > 74 > 17 > 3245-3261

How Ras, and in particular its most abundant oncogenic isoform K-Ras4B, is activated and signals in proliferating cells, poses some of the most challenging questions in cancer cell biology. In this paper, we ask how intrinsically disordered regions in K-Ras4B and its effectors help promote proliferative signaling. Conformational disorder allows spanning long distances, supports hinge motions, promotes...

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Polyubiquitin-Photoactivatable Crosslinking Reagents for Mapping Ubiquitin Interactome Identify Rpn1 as a Proteasome Ubiquitin-Associating Subunit

Michal Chojnacki, Wissam Mansour, Dharjath S. Hameed, Rajesh K. Singh, more

Cell Chemical Biology > 2017 > 24 > 4 > 443-457.e6

Ubiquitin (Ub) signaling is a diverse group of processes controlled by covalent attachment of small protein Ub and polyUb chains to a range of cellular protein targets. The best documented Ub signaling pathway is the one that delivers polyUb proteins to the 26S proteasome for degradation. However, studies of molecular interactions involved in this process have been hampered by the transient and hydrophobic...

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Identification of primary and secondary UBA footprints on the surface of ubiquitin in cell‐mimicking crowded solution

Francesca Munari, Andrea Bortot, Serena Zanzoni, Mariapina D'Onofrio, more

FEBS Letters > 591 > 7 > 979 - 990

Despite significant advancements in our understanding of ubiquitin‐mediated signaling, the influence of the intracellular environment on the formation of transient ubiquitin‐partner complexes remains poorly explored. In our work, we introduce macromolecular crowding as a first level of complexity toward the imitation of a cellular environment in the study of such interactions. Using NMR spectroscopy,...

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Exploring Polyubiquitin as a Flexible Multiple-Ligand Binding Platform

David Fushman

Structure > 2017 > 25 > 1 > 1-3

Linear (head-to-tail linked) polyubiquitin chains play a key role in the regulation of NF-κB signaling. In this issue of Structure, Lin et al. (2017) shed light on how linear tri-ubiquitin binds to ABIN2, a molecule that shares ubiquitin-binding properties of NEMO, the key activator of NF-κB.

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Characterizing polyubiquitinated forms of the neurodegenerative ubiquitin mutant UBB⁺¹

Michal Chojnacki, Daoning Zhang, Monika Talarowska, Piotr Gałecki, more

FEBS Letters > 590 > 24 > 4573 - 4585

The ubiquitin mutant UBB⁺¹ has been identified as a hallmark of neurodegenerative diseases. In this study, we characterize polyubiquitinated forms of UBB⁺¹ in vitro and from patient samples. The ability of UBB⁺¹ to be readily ubiquitinated by several E2 enzymes provided a mechanism for the controlled synthesis and purification of defined conjugates. This allowed us to utilize polyUb–UBB⁺¹ conjugates...

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RASSF5: An MST activator and tumor suppressor in vivo but opposite in vitro

Tsung-Jen Liao, Chung-Jung Tsai, Hyunbum Jang, David Fushman, more

Current Opinion in Structural Biology > 2016 > 41 > C > 217-224

Is RASSF5 a tumor suppressor or activator? RASSF5 links K-Ras and the Hippo pathway. Hippo's signaling promotes YAP1 phosphorylation and degradation. YAP1 overexpression promotes cancer. Most reports point to RASSF5 suppressing cancer; however, some point to its promoting cancer. Our mechanistic view explains how RASSF5 can activate MST1/2 and suppress cancer in vivo; but inhibits MST1/2 in vitro...

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Preparing to read the ubiquitin code: top‐down analysis of unanchored ubiquitin tetramers

Amanda E. Lee, Lucia Geis‐Asteggiante, Emma K. Dixon, Meredith Miller, more

Journal of Mass Spectrometry > 51 > 8 > 629 - 637

The characterization of polyubiquitin chains has been an analytical challenge for several decades. It has been shown that anchored and unanchored polyubiquitin chains with different isopeptide linkages and lengths exhibit a wide range of profoundly different cellular functions. However, structure function studies have been hindered by the difficulty of characterizing these complex chain structures...

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Preparing to read the ubiquitin code: characterization of ubiquitin trimers by top‐down mass spectrometry

Amanda E. Lee, Lucia Geis‐Asteggiante, Emma K. Dixon, Yeji Kim, more

Journal of Mass Spectrometry > 51 > 4 > 315 - 321

The profound effects of ubiquitination on the movement and processing of cellular proteins depend exquisitely on the structures of monoubiquitin and polyubiquitin modifications. Unconjugated polyubiquitins also have a variety of intracellular functions. Structures and functions are not well correlated yet, because the structures of polyubiquitins and polyubiquitin modifications of proteins are difficult...

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Linkage via K27 Bestows Ubiquitin Chains with Unique Properties among Polyubiquitins

Carlos A. Castañeda, Emma K. Dixon, Olivier Walker, Apurva Chaturvedi, more

Structure > 2016 > 24 > 3 > 423-436

Polyubiquitination, a critical protein post-translational modification, signals for a diverse set of cellular events via the different isopeptide linkages formed between the C terminus of one ubiquitin (Ub) and the ɛ-amine of K6, K11, K27, K29, K33, K48, or K63 of a second Ub. We assembled di-ubiquitins (Ub₂) comprising every lysine linkage and examined them biochemically and structurally. Of these,...

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DNA-Damage-Inducible 1 Protein (Ddi1) Contains an Uncharacteristic Ubiquitin-like Domain that Binds Ubiquitin

Urszula Nowicka, Daoning Zhang, Olivier Walker, Daria Krutauz, more

Structure > 2015 > 23 > 3 > 542-557

Ddi1 belongs to a family of shuttle proteins targeting polyubiquitinated substrates for proteasomal degradation. Unlike the other proteasomal shuttles, Rad23 and Dsk2, Ddi1 remains an enigma: its function is not fully understood and structural properties are poorly characterized. We determined the structure and binding properties of the ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains of...

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The Association Landscape of Ubiquitin Dimerization

Haiqing Zhao, David Fushman, Garegin A. Papoian

Biophysical Journal > 2015 > 108 > 2 Supplement 1 > 519a

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Information content of long-range NMR data for the characterization of conformational heterogeneity

Witold Andrałojć, Konstantin Berlin, David Fushman, Claudio Luchinat, more

Journal of Biomolecular NMR > 2015 > 62 > 3 > 353-371

Long-range NMR data, namely residual dipolar couplings (RDCs) from external alignment and paramagnetic data, are becoming increasingly popular for the characterization of conformational heterogeneity of multidomain biomacromolecules and protein complexes. The question addressed here is how much information is contained in these averaged data. We have analyzed and compared the information content of...

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Preparing to read the ubiquitin code: a middle‐out strategy for characterization of all lysine‐linked diubiquitins

Amanda E. Lee, Carlos A. Castañeda, Yan Wang, David Fushman, more

Journal of Mass Spectrometry > 49 > 12 > 1272 - 1278

Multiple studies demonstrate that ubiquitination of proteins codes for regulation of cell differentiation, apoptosis, endocytosis and many other cellular functions. There is great interest in and considerable effort being given to defining the relationships between the structures of polyubiquitin modifications and the fates of the modified proteins. Does each ubiquitin modification achieve a specific...

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Nonenzymatic Rubylation and Ubiquitination of Proteins for Structural and Functional Studies

Rajesh K. Singh, Adithya Sundar, David Fushman

Angewandte Chemie > 126 > 24 > 6234 - 6239

Uncovering the mechanisms that allow conjugates of ubiquitin (Ub) and/or Ub‐like (UBL) proteins such as Rub1 to serve as distinct molecular signals requires the ability to make them with native connectivity and defined length and linkage composition. A novel, effective, and affordable strategy for controlled chemical assembly of fully natural UBL–Ub, Ub–UBL, and UBL–UBL conjugates from recombinant...

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Nonenzymatic Rubylation and Ubiquitination of Proteins for Structural and Functional Studies

Rajesh K. Singh, Adithya Sundar, David Fushman

Angewandte Chemie International Edition > 53 > 24 > 6120 - 6125

Uncovering the mechanisms that allow conjugates of ubiquitin (Ub) and/or Ub‐like (UBL) proteins such as Rub1 to serve as distinct molecular signals requires the ability to make them with native connectivity and defined length and linkage composition. A novel, effective, and affordable strategy for controlled chemical assembly of fully natural UBL–Ub, Ub–UBL, and UBL–UBL conjugates from recombinant...

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Alanine Scan of Core Positions in Ubiquitin Reveals Links between Dynamics, Stability, and Function

Shirley Y. Lee, Lester Pullen, Daniel J. Virgil, Carlos A. Castañeda, more

Journal of Molecular Biology > 2014 > 426 > 7 > 1377-1389

Mutations at solvent-inaccessible core positions in proteins can impact function through many biophysical mechanisms including alterations to thermodynamic stability and protein dynamics. As these properties of proteins are difficult to investigate, the impacts of core mutations on protein function are poorly understood for most systems. Here, we determined the effects of alanine mutations at all...

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Modifying the Vicinity of the Isopeptide Bond To Reveal Differential Behavior of Ubiquitin Chains with Interacting Proteins: Organic Chemistry Applied to Synthetic Proteins

Najat Haj‐Yahya, Mahmood Haj‐Yahya, Carlos A. Castañeda, Liat Spasser, more

Angewandte Chemie > 125 > 42 > 11355 - 11359

Aus allen Richtungen: Durch chemische Proteinsynthese wurden 14 Diubiquitin‐Analoga mit Modifikationen in der Umgebung der Isopeptidbindung hergestellt und auf ihr Verhalten gegenüber Deubiquitinasen und Ubiquitinbindedomänen untersucht. Die Ergebnisse schaffen die Grundlage für die Erzeugung von spezifischen Sonden zur Untersuchung der Wechselwirkungen dieser Ketten mit ubiquitinbindenden Proteinen.

INFONA - science communication portal

Search results for: David Fushman

Top‐down analysis of novel synthetic branched proteins

Autoinhibition in Ras effectors Raf, PI3Kα, and RASSF5: a comprehensive review underscoring the challenges in pharmacological intervention

Structural Basis for the Inhibitory Effects of Ubistatins in the Ubiquitin-Proteasome Pathway

Intrinsic protein disorder in oncogenic KRAS signaling

Polyubiquitin-Photoactivatable Crosslinking Reagents for Mapping Ubiquitin Interactome Identify Rpn1 as a Proteasome Ubiquitin-Associating Subunit

Identification of primary and secondary UBA footprints on the surface of ubiquitin in cell‐mimicking crowded solution

Exploring Polyubiquitin as a Flexible Multiple-Ligand Binding Platform

Characterizing polyubiquitinated forms of the neurodegenerative ubiquitin mutant UBB⁺¹

RASSF5: An MST activator and tumor suppressor in vivo but opposite in vitro

Preparing to read the ubiquitin code: top‐down analysis of unanchored ubiquitin tetramers

Preparing to read the ubiquitin code: characterization of ubiquitin trimers by top‐down mass spectrometry

Linkage via K27 Bestows Ubiquitin Chains with Unique Properties among Polyubiquitins

DNA-Damage-Inducible 1 Protein (Ddi1) Contains an Uncharacteristic Ubiquitin-like Domain that Binds Ubiquitin

The Association Landscape of Ubiquitin Dimerization

Information content of long-range NMR data for the characterization of conformational heterogeneity

Preparing to read the ubiquitin code: a middle‐out strategy for characterization of all lysine‐linked diubiquitins

Nonenzymatic Rubylation and Ubiquitination of Proteins for Structural and Functional Studies

Nonenzymatic Rubylation and Ubiquitination of Proteins for Structural and Functional Studies

Alanine Scan of Core Positions in Ubiquitin Reveals Links between Dynamics, Stability, and Function

Modifying the Vicinity of the Isopeptide Bond To Reveal Differential Behavior of Ubiquitin Chains with Interacting Proteins: Organic Chemistry Applied to Synthetic Proteins

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