Nothing is solid about proteins. Governing rules and established laws are constantly broken. As an example, the last decade and a half have witnessed the fall of one of the major paradigms in structural biology. Contrarily to the more than a century-old belief that the unique function of a protein is determined by its unique structure, which, in its turn, is defined by the unique amino acid sequence, many biologically active proteins lack stable tertiary and/or secondary structure either entirely or at their significant parts. Such intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered domains and functional IDP regions (IDPRs) are highly abundant in nature, and many of them are associated with various human diseases. Such disordered proteins and regions are very different from ordered and well-structured proteins and domains at a variety of levels and possess well-recognizable biases in their amino acid compositions and amino acid sequences. A characteristic feature of these proteins is their exceptional structural heterogeneity, where different parts of a given polypeptide chain can be ordered (or disordered) to different degrees. As a result, a typical IDP/IDPR contains a multitude of potentially foldable, partially foldable, differently foldable or not foldable structural segments. This distribution of conformers is constantly changing in time, where a given segment of a protein molecule has different structures at different time points. The distribution is also constantly changing in response to changes in the environment. This mosaic structural organization is crucial for their functions and many IDPs are engaged in biological functions that rely on high conformational flexibility and that are not accessible to proteins with unique and fixed structures. As a result, the functional repertoire of IDPs complements that of ordered proteins, with IDPs/IDPRs being often involved in regulation, signaling and control. This Sprenger Briefs volume is dedicated to IDPs and IDPRs and an attempt is made to compress a massive amount of knowledge and into a digest that aims to be of use to those wishing a fast entry into this promising field of structural biology.

Intrinsically Disordered Proteins

This perspective is partly review and partly proposal. N-degrons and C-degrons are degradation signals whose main determinants are, respectively, the N-terminal and C-terminal residues of cellular proteins. N-degrons and C-degrons include, to varying extents, adjoining sequence motifs, and also internal lysine residues that function as polyubiquitylation sites. Discovered in 1986, N-degrons were the first degradation signals in short-lived proteins. A particularly large set of C-degrons was discovered in 2018. We describe multifunctional proteolytic systems that target N-degrons and C-degrons. We also propose to denote these systems as “N-degron pathways” and “C-degron pathways.” The former notation replaces the earlier name “N-end rule pathways.” The term “N-end rule” was introduced 33 years ago, when only some N-terminal residues were thought to be destabilizing. However, studies over the last three decades have shown that all 20 amino acids of the genetic code can act, in cognate sequence contexts, as destabilizing N-terminal residues. Advantages of the proposed terms include their brevity and semantic uniformity for N-degrons and C-degrons. In addition to being topologically analogous, N-degrons and C-degrons are related functionally. A proteolytic cleavage of a subunit in a multisubunit complex can create, at the same time, an N-degron (in a C-terminal fragment) and a spatially adjacent C-degron (in an N-terminal fragment). Consequently, both fragments of a subunit can be selectively destroyed through attacks by the N-degron and C-degron pathways.

https://www.pnas.org/content/pnas/116/2/358.full.pdf

N-degron and C-degron pathways of protein degradation

Macroautophagy and microautophagy are highly conserved eukaryotic cellular processes that degrade cytoplasmic material in lysosomes. Both pathways involve characteristic membrane dynamics regulated by autophagy-related proteins and other molecules, some of which are shared between the two pathways. Over the past few years, the application of new technologies, such as cryo-electron microscopy, coevolution-based structural prediction and in vitro reconstitution, has revealed the functions of individual autophagy gene products, especially in autophagy induction, membrane reorganization and cargo recognition. Concomitantly, mutations in autophagy genes have been linked to human disorders, particularly neurodegenerative diseases, emphasizing the potential pathogenic implications of autophagy defects. Accumulating genome data have also illuminated the evolution of autophagy genes within eukaryotes as well as their transition from possible ancestral elements in prokaryotes. 

/pdf/autophagy-genes-in-biology-and-disease-2wt2vt2u.pdf

Autophagy genes in biology and disease

Autophagy is fundamental for cell and organismal health. Two types of autophagy are conserved in eukaryotes: macroautophagy and microautophagy. During macroautophagy, autophagosomes deliver cytoplasmic constituents to endosomes or lysosomes, whereas during microautophagy lytic organelles take up cytoplasm directly. While macroautophagy has been investigated extensively, microautophagy has received much less attention. Nonetheless, it has become clear that microautophagy has a broad range of functions in biosynthetic transport, metabolic adaptation, organelle remodeling and quality control. This Review discusses the selective and non-selective microautophagic processes known in yeast, plants and animals. Based on the molecular mechanisms for the uptake of microautophagic cargo into lytic organelles, I propose to distinguish between fission-type microautophagy, which depends on ESCRT proteins, and fusion-type microautophagy, which requires the core autophagy machinery and SNARE proteins. Many questions remain to be explored, but the functional versatility and mechanistic diversity of microautophagy are beginning to emerge.

/pdf/microautophagy-distinct-molecular-mechanisms-handle-cargoes-59wc7fzsmm.pdf

Microautophagy - distinct molecular mechanisms handle cargoes of many sizes.

The emerging mechanisms and functions of microautophagy

ER‐phagy, the selective autophagy of endoplasmic reticulum (ER), safeguards organelle homeostasis by eliminating misfolded proteins and regulating ER size. ER‐phagy can occur by macroautophagic and microautophagic mechanisms. While dedicated machinery for macro‐ER‐phagy has been discovered, the molecules and mechanisms mediating micro‐ER‐phagy remain unknown. Here, we first show that micro‐ER‐phagy in yeast involves the conversion of stacked cisternal ER into multilamellar ER whorls during microautophagic uptake into lysosomes. Second, we identify the conserved Nem1‐Spo7 phosphatase complex and the ESCRT machinery as key components for micro‐ER‐phagy. Third, we demonstrate that macro‐ and micro‐ER‐phagy are parallel pathways with distinct molecular requirements. Finally, we provide evidence that the ESCRT machinery directly functions in scission of the lysosomal membrane to complete the microautophagic uptake of ER. These findings establish a framework for a mechanistic understanding of micro‐ER‐phagy and, thus, a comprehensive appreciation of the role of autophagy in ER homeostasis.

/pdf/escrt-machinery-mediates-selective-microautophagy-of-2ohyrws8li.pdf

ESCRT machinery mediates selective microautophagy of endoplasmic reticulum in yeast

SHRED Is a Regulatory Cascade that Reprograms Ubr1 Substrate Specificity for Enhanced Protein Quality Control during Stress.

ER-phagy, the selective autophagy of endoplasmic reticulum (ER), safeguards organelle homeostasis by eliminating misfolded proteins and regulating ER size. ER-phagy can occur by macroautophagic and microautophagic mechanisms. While dedicated machinery for macro-ER-phagy has been discovered, the molecules and mechanisms mediating micro-ER-phagy remain unknown. Here, we first show that micro-ER-phagy in yeast involves the conversion of stacked cisternal ER into multilamellar ER whorls during microautophagic uptake into lysosomes. Second, we identify the conserved Nem1-Spo7 phosphatase complex and ESCRT proteins as key components for micro-ER-phagy. Third, we demonstrate that macro- and micro-ER-phagy are parallel pathways with distinct molecular requirements. Finally, we provide evidence that ESCRT proteins directly function in scission of the lysosomal membrane to complete the microautophagic uptake of ER. These findings establish a framework for a mechanistic understanding of micro-ER-phagy and, thus, a comprehensive appreciation of the role of autophagy in ER homeostasis.

https://biorxiv.org/content/biorxiv/early/2019/06/05/661306.full-text.pdf

ESCRT machinery mediates selective microautophagy of endoplasmic reticulum

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ESCRT machinery mediates selective microautophagy of endoplasmic reticulum in yeast

SHRED Is a Regulatory Cascade that Reprograms Ubr1 Substrate Specificity for Enhanced Protein Quality Control during Stress.

ESCRT machinery mediates selective microautophagy of endoplasmic reticulum