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In the Ub sandwich technique, by Glenn Turner then a graduate student and myself , the polypeptide to be examined for cotranslational degradation, termed B , is sandwiched between two reporter domains, A and C. The resulting decrease in C Ub relative to A Ub reflects the presence and extent of cotranslational degradation of the B domain Thus, the folding of nascent proteins, including abnormal ones, may be in kinetic competition with pathways that target these proteins for degradation cotranslationally.

Our current focus is the N-end rule pathway. We study it in yeast S. Over the last decade, this work led to discoveries of the pathway's functions in eukaryotes, whereas the physiology of bacterial N-end rule pathways is still unknown, despite advances in their mechanistic understanding 80 , — Our studies of the mouse N-end rule pathway were led by Dr. Yong Tae Kwon, who now works in his own laboratory at the University of Pittsburgh. Thus far, Kwon's and my laboratories are the only ones that focus on the N-end rule pathway. In addition to the possibility that these interactions underlie a route for delivery of ubiquitylated substrates to the proteasome, our results suggested that at least some Ub ligases may target their substrates while in a complex with the 26 S proteasome.

Other groups reported that several other Ub ligases also interacted with the 26 S proteasome. In , Xie and I showed that a mutant S. Also in , Jun Sheng then a postdoctoral student and I dissected the degradation signal of c-MOS, a kinase and regulator of oocyte maturation Data obtained by others suggested that the N-terminal Pro residue of c-MOS may be a destabilizing residue that targets c-MOS for destruction in frog oocytes. Our degradation assays involved microinjection of plasmids that expressed wild-type or mutant c-MOS in Xenopus oocytes.

These and other results showed that the dependence of c-MOS degradation on the N-terminal Pro residue is caused by a Pro-mediated down-regulation of the net phosphorylation of Ser 2 , a modification that halts c-MOS degradation. In other words, the N-terminal Pro is, operationally, a stabilizing residue in the N-end rule, in agreement with our earlier findings The N-end rule has a hierarchic structure Fig. In eukaryotes, N-terminal Asn and Gln are tertiary destabilizing residues in that they function through their enzymatic deamidation to yield the secondary destabilizing N-terminal residues Asp and Glu , The destabilizing activity of N-terminal Asp and Glu requires their conjugation to Arg, one of the primary destabilizing residues, by ATE1 -encoded R-transferases of the N-end rule pathway Fig.

In , Kwon, Anna Kashina then a postdoctoral student , and I cloned mouse ATE1 and found that it encodes at least two splicing-derived isoforms of R-transferase In , Rong-Gui Cory Hu, Christopher Brower postdoctoral students in the lab , and their colleagues identified and characterized six splicing-derived isoforms of mouse R-transferase 88 , a pattern that remains to be understood functionally. In mammals and other eukaryotes that produce nitric oxide NO , the set of arginylated N-terminal residues contains not only Asp and Glu but also N-terminal Cys 16 , which is arginylated after its oxidation to Cys sulfinate or Cys sulfonate, as shown in by Kwon, Kashina, Hu, Ilia Davydov then a postdoctoral student , Fangyong Du then a graduate student , and myself Fig.

Autophagy: machinery and regulation

The N-end rule pathway is thus a sensor of NO, through the ability of this pathway to destroy proteins with N-terminal Cys, at rates controlled by NO, O 2 , and their derivatives. In , Davydov and I found that RGS4 was degraded by the N-end rule pathway in reticulocyte extracts , before we learned that this degradation requires NO and oxygen 87 , An N-degron is produced from a pre-N-degron through a proteolytic cleavage. MetAP proteases remove Met from the N terminus of a newly formed protein only if the residue at position 2, to be made N-terminal after cleavage, has a small enough side chain.

Consequently, of the 13 destabilizing residues in the mammalian N-end rule Fig. Note that any destabilizing residue , including Cys, can be made N-terminal through internal cleavages of proteins by other proteases such as separases, caspases, and calpains Fig. There are many more potential N-end rule substrates that may be produced by other proteolytic cleavages in cellular proteins.

In multicellular eukaryotes, the deamidation branch of the N-end rule pathway bifurcates: a distinct N-terminal amidase, NTAN1, is specific for N-terminal Asn, whereas another amidase which remains to be identified deamidates N-terminal Gln Fig. In , Sergei Grigoryev then a postdoctoral student and colleagues in the lab collaborated with the laboratory of Ralph Bradshaw University of California, Irvine to clone and characterize the mouse NTAN1 amidase The biological role of yeast NTA1 remains to be discovered, as S.

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E3 Ub ligases of the N-end rule pathway, called N-recognins 57 , recognize bind to primary destabilizing N-terminal residues Fig. UBR1 contains at least three substrate-binding sites, which were identified and analyzed over the years by colleagues in the lab, most recently in by Zanxian Xia, Ailsa Webster, and Michel Ghislain then postdoctoral students , Konstantin Piatkov a postdoctoral student in the lab , Du, and myself The third binding site of UBR1 targets proteins through their internal non-N-terminal degrons.

A physiological function of this multisite design of UBR1 was discovered in — by Turner, Du, Christopher Byrd then a graduate student , and myself , , In , Byrd, Turner, and I identified the yeast transcriptional repressor CUP9 as a short-lived substrate of the N-end rule pathway and a down-regulator of PTR2 , which encodes the major transporter of short peptides This result explained the earlier finding by the laboratory of Jeffrey Becker University of Tennessee, Knoxville that the import of peptides in S.


This site of UBR1 can be allosterically activated through a conformational change that is caused by the binding of short peptides bearing destabilizing N-terminal residues to the other two types 1 and 2 binding sites of UBR1 , The resulting reversal of UBR1 autoinhibition by imported peptides accelerates the UBR1-mediated ubiquitylation of CUP9, leads to its faster degradation and consequently to a derepression of the transporter-encoding PTR2 gene , This positive feedback circuit, mediated by short peptides and the N-end rule pathway, allows cells to detect the presence of extracellular peptides and to react by increasing their uptake.

Between and , Kwon and colleagues in my lab constructed and analyzed mouse strains that lacked specific components of the N-end rule pathway Fig. These studies and our later collaborations with the Kwon laboratory have revealed informative phenotypes of mouse mutants that further expanded the pathway's functional range. In , Hu, Haiqing Wang then a postdoctoral student , Xia, and I discovered that the N-end rule pathway is a sensor of heme In addition, hemin induces the proteasome-mediated degradation of R-transferase in vivo.

This proteolytic system, a sensor of short peptides, NO, and oxygen, is now a sensor of heme as well One function of the N-end rule pathway may be to coordinate the activities of effectors, both reacting to and controlling the redox dynamic of heme, oxygen, NO, and thiols, in part through the conditional degradation of specific transcriptional regulators e.

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CUP9 and c-Fos and regulators of G-proteins e. The functions of the N-end rule pathway include the sensing of NO, oxygen, short peptides, and heme; maintenance of the high fidelity of chromosome segregation in eukaryotes from fungi to mammals through the degradation of a separase-produced fragment of the cohesin subunit; regulation of peptide import through the degradation modulated by peptides of S. In , a collaborative study with Kwon's and my laboratories that was led by Dr.

Despite their multiplicity and broad range, the known functions of the N-end rule pathway are still the tip of the iceberg. Several fascinating phenotypes of mouse N-end rule mutants remain to be understood.

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This is also true for other, more overt and severe defects in other mouse N-end rule mutants and in human patients with JBS In , my interest in useful terminology e. Besides their usefulness as separate terms for sequence versus spatial similarities, the rigor-conferring advantage of sequelog and spalog is their evolutionary neutrality , in contrast to often unproven evolutionary links implied by homolog, ortholog, and paralog.

Helpful derivatives of, for example, sequelog are sequelogy sequence similarity and sequelogous similar to another sequence. Spalog and sequelog fill a lacuna in the existing terminology.

These terms would clarify and streamline discourses about similarity The coming revolution in medicine will involve not only qualitatively better ways to do surgery but also drug-based therapies that will take into account, at last, the massive interconnectedness and redundancy of molecular circuits in living cells.

Single-compound and even multi-compound drugs of today are incapable of such finesse. Therefore, even otherwise useful drugs exhibit undesirable side effects. Yet another problem is our continuing helplessness in containing let alone curing major human cancers once they spread beyond a surgeon's knife. The problem is exacerbated by the genomic instability of many, possibly most, cancers.

This property increases the heterogeneity of malignant cells in the course of tumor progression or anticancer treatment and is one reason for the failure of most cancer therapies. A few relatively rare cancers can often be cured through chemotherapy but require cytotoxic treatments of a kind that cause severe side effects and are themselves carcinogenic. Recent advances, including the use of anti-angiogenic compounds and inhibitors of specific kinases, hold the promise of curative therapies.

Nevertheless, major human cancers are still incurable once they have metastasized. A article described another design, of small compounds whose activity can be modulated by more than one protein ligand at the same time We eventually decided not to implement these approaches in the lab because I thought, perhaps mistakenly, that the resulting drugs would not be efficacious enough in a clinical setting. In , I proposed a new approach to cancer therapy that involves homozygous DNA deletions Such deletions are present in many possibly most cancers and differ from any other attribute of a cancer cell by the fact that a homozygous deletion HD cannot revert.

Hence the idea of a treatment that exclusively homes in on cells that lack specific DNA sequences that are present in normal cells. If this proves possible, a resulting therapy may be entirely specific for cancer cells and thus not only curative but substantially free of side effects as well. Nevertheless, an HD-specific regimen is feasible, on paper so far The DST strategy brings together, in a novel way, both existing and new methodologies, including the Ub fusion technique, the split-Ub assay, zinc-finger DNA-recognizing proteins, and split restriction nucleases.

The DST strategy also employs a new feedback mechanism that receives input from a circuit operating as a Boolean OR gate and involves the activation of split nucleases, which destroy the DST vector in normal non-target cells. The logic of DST makes possible an incremental and essentially unlimited increase in the selectivity of treatment If the substantial complexity of DST-type strategies is unavoidable this remains to be determined , approaches of this kind might be a harbinger of therapies to come.

The virtues of simplicity notwithstanding, a complex problem, such as an assured cure of cancer, or a selective elimination of damaged e. Can small compounds, with their inherently low informational content, ever enable a definitive cure of cancer that is free of collateral damage? The notion that underlies and motivated the DST strategy is that a curative, side effect-free treatment may require polymer-scale, multitarget, Boolean-type circuits, i.

The task at hand is to address the validity of this assumption. Work on the DST strategy is under way in the lab. My laboratory has been at Caltech for the past 16 years. The decision to move here from MIT was prompted by an unexpected invitation. I showed it to my wife Vera, and we visited Caltech in February The scientific quality of Caltech, the charms of Pasadena's subtropical climate, and the warm reception by colleagues were compelling to both of us. Caltech is a great place, similar to MIT in all respects but smaller.

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Vera and I live in La Canada, a hamlet on a mountainside near Pasadena. At 61, I have already traveled through the bulk of life span allotted to us by evolution. Curiously, the Ub system plays a major role in determining that life span. Moreover, Ub-dependent processes underlie just about everything a living cell does. An account of our discoveries through which this fact became known and understood is the main chapter of this recollection. A scientist's life, its adventures and misadventures, its loves and conflicts, is largely incidental, tangential to one's contribution, in a profession that tends to swallow a person whole.

Our propensity to be curious about other people obscures the fact that it is essentially immaterial that Isaac Newton was not a kind man or that Johannes Kepler had to defend his mother in court against the charge of being a witch she was acquitted. To think of Newton or Kepler is to think of their work.