α-Helical Coiled-coil Oligomerization Domains Are Almost Ubiquitous in the Collagen Superfamily

McAlinden, Audrey; Smith, Thomasin A.; Sandell, Linda J.; Ficheux, Damien; Parry, David; Hulmes, David J.S.

doi:10.1074/jbc.m302429200

Cited by 78 publications

(80 citation statements)

References 66 publications

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“…7, which is published as supporting information on the PNAS web site, potential interhelical g Arg to eЈ Glu salt bridges are found in many other short (15-50 aa in length) parallel trimeric coiled-coil domains of intracellular, extracellular, transmembrane, viral, and synthetic proteins. Several members of these autonomous coiled coils are well characterized (9,30,31,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Based on the alignment, the sequence motif R 1 -h 2 -x 3 -x 4 -h 5 -E 6 can be deduced (R ϭ Arg; E ϭ Glu, L ϭ Leu; h 1 ϭ Ile, Leu, Val, Met; h 2 ϭ Leu, Ile, Val; x ϭ any amino acid residue).…”

Section: The Sequence Motif R-h-x-x-h-e Is Conserved Among Parallel Tmentioning

confidence: 99%

A conserved trimerization motif controls the topology of short coiled coils

Kammerer

Kostrewa

Progias

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

108

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In recent years, short coiled coils have been used for applications ranging from biomaterial to medical sciences. For many of these applications knowledge of the factors that control the topology of the engineered protein systems is essential. Here, we demonstrate that trimerization of short coiled coils is determined by a distinct structural motif that encompasses specific networks of surface salt bridges and optimal hydrophobic packing interactions. The motif is conserved among intracellular, extracellular, viral, and synthetic proteins and defines a universal molecular determinant for trimer formation of short coiled coils. In addition to being of particular interest for the biotechnological production of candidate therapeutic proteins, these findings may be of interest for viral drug development strategies.protein engineering ͉ sequence-to-structure rules ͉ protein-protein interaction ͉ salt bridges ͉ x-ray crystallography T he potential of short ␣-helical coiled coils for protein engineering, biotechnological, biomaterial, basic research, and medical applications has recently been recognized (1-12). The wide range of applications underscores the need for topological control of coiled-coil peptides. Although seemingly simple, coiled coils can form a variety of different assemblies ranging from dimers to pentamers (13,14). Furthermore, coiled coils can form homomers or heteromers with their chains arranged in a parallel or antiparallel fashion. To understand how side-chainside-chain interactions determine a particular structure, it is important to discriminate the factors responsible for specific interhelical interactions from those that are common to all coiled coils such as the heptad repeat.It is generally acknowledged that the detailed packing geometry of hydrophobic core residues correlates with the oligomerization state (15,16). In dimers the side chains of the residues at a and d positions pack in a manner termed parallel and perpendicular, respectively. In the four-stranded state the dimer mode is reversed. Trimeric coiled coils are characterized by an intermediate geometry of these residues, termed acute. Previous studies found that these oligomerization states are determined in particular by the distribution of isoleucine and leucine residues that prefer the parallel and acute, and the acute and perpendicular geometries, respectively (15, 16).Buried polar residues in hydrophobic interfaces also play an important role in determining the number and orientation of strands in coiled coils. Many two-stranded leucine zippers of transcription regulators contain at least one conserved polar residue. Frequently an asparagine or a lysine residue occupies heptad position a toward the center of the sequence, suggesting a common mechanism for determining dimer specificity in these molecules (17). Polar residues like glutamine and threonine at positions a and d, respectively, can favor trimer formation (18,19). Interhelical interactions between side chains of residues at the e and g positions as well as the packi...

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Section: The Sequence Motif R-h-x-x-h-e Is Conserved Among Parallel Tmentioning

confidence: 99%

A conserved trimerization motif controls the topology of short coiled coils

Kammerer

Kostrewa

Progias

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

108

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“…In nature, α‐helical bundles such as helix‐loop‐helix (HLH) and helix‐turn‐helix motifs are frequently observed in coiled coil proteins 16. The antiparallel LK dimer has a close resemblance to that of natural HLH motifs with the exception of the fact that the monomeric units in the dimer are linked via disulfide bonds.…”

Section: Resultsmentioning

confidence: 99%

Multimeric Amphipathic α‐Helical Sequences for Rapid and Efficient Intracellular Protein Transport at Nanomolar Concentrations

Chong

Nam

et al. 2018

Advanced Science

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An amphipathic leucine (L) and lysine (K)‐rich α‐helical peptide is multimerized based on helix‐loop‐helix structures to maximize the penetrating activities. The multimeric LK‐based cell penetrating peptides (LK‐CPPs) can penetrate cells as protein‐fused forms at 100–1000‐fold lower concentrations than Tat peptide. The enhanced penetrating activity is increased through multimerization by degrees up to the tetramer level. The multimeric LK‐CPPs show rapid cell penetration through macropinocytosis at low nanomolar concentrations, unlike the monomeric LK, which have slower penetrating kinetics at much higher concentrations. The heparan sulfate proteoglycan (HSPG) receptors are highly involved in the rapid internalization of multimeric LK‐CPPs. As a proof of concept of biomedical applications, an adipogenic transcription factor, peroxisome proliferator‐activated receptor gamma 2 (PPAR‐γ 2), is delivered into preadipocytes, and highly enhanced expression of adipogenic genes at nanomolar concentrations is induced. The multimeric CPPs can be a useful platform for the intracellular delivery of bio‐macromolecular reagents that have difficulty with penetration in order to control biological reactions in cells at feasible concentrations for biomedical purposes.

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“…Recent studies have suggested two separate motifs important for the correct folding of collagen type XIII: one region in the NC1 domain and one in the NC3 domain (38). These motifs are conserved in collagen types XXIII and XXV and have therefore been suggested to be of importance also for these transmembrane collagens (38,39). In accordance with a previous report (18), CLAC formed dimers and trimers even though the splice variant expressed in this study lacks parts of the sequences of the COL3 and NC4 domains (residues 589 -640, according to the numbering of GenBank TM /EBI accession number AF293341).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Alzheimer's Disease-associated CLAC Protein and Identification of an Amyloid β-Peptide-binding Site

Söderberg

Kakuyama

Möller

et al. 2005

Journal of Biological Chemistry

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Amyloid ␤-peptide (A␤) deposition into amyloid plaques is one of the invariant neuropathological features of Alzheimer's disease. Other proteins co-deposit with A␤ in plaques, and one recently identified amyloidassociated protein is the collagen-like Alzheimer amyloid plaque component CLAC. It is not known how CLAC deposition affects A␤ plaque genesis and the progress of the disease. Here, we studied the in vitro properties of CLAC purified from a mammalian expression system. CLAC displays features characteristic of a collagen protein, e.g. it forms a partly protease-resistant triple-helical structure, exhibits an intermediate affinity for heparin, and is glycosylated. Purified CLAC was also used to investigate the interaction between CLAC and A␤. Using a solid-phase binding assay, we show that CLAC bound with a similar affinity to aggregates formed by A␤-(1-40) and A␤-(1-42) and that the interaction was impaired by increasing salt concentrations. An 8-residue-long sequence located in non-collagenous domain 2 of CLAC was found to be crucial for the interaction with A␤. These findings may be useful for future therapeutic interventions aimed at finding compounds that modulate the binding of CLAC to A␤ deposits.Alzheimer's disease (AD) 1 is a progressive neurodegenerative disorder characterized by selective neuronal loss associated with intracellular neurofibrillary tangle formation and extracellular amyloid plaques (1). The major constituents of the amyloid plaques are fibrils formed from the 40 -42-residue amyloid ␤-peptide (A␤) (2). A␤ is generated from the type I transmembrane Alzheimer amyloid precursor protein by two consecutive proteolytic cleavages. The aspartyl protease ␤-secretase BACE generates the N terminus of A␤, whereas the C terminus results from the proteolytic action of the ␥-secretase complex (3). Data from genetic and biochemical studies suggest that accumulation of the longer and more amyloidogenic species of A␤, A␤42, is a primary event in the development of AD (4). For instance, autosomal dominant forms of early-onset familial AD appear to result from an increased production of A␤42 (5), and total levels of brain A␤42 correlate with cognitive decline in AD (6).Several proteins other than A␤ have been shown by immunohistochemical methods to be associated with AD amyloid plaques (7). Some of these plaque-associated proteins, e.g. apolipoprotein J (8, 9), apolipoprotein E (10), and ␣ 1 -antichymotrypsin (11), modulate peptide aggregation. In addition, constituents of the extracellular brain matrix, e.g. the heparan sulfate proteoglycans (12-14), laminin (15, 16), and collagen type IV (17), accumulate in amyloid plaques and bind to A␤. The appearance of some of these plaque-associated proteins may be indicative of a local inflammatory response to the amyloid, and others may promote A␤ aggregation or stabilize the amyloid plaques. Recently, a novel plaque-associated protein, CLAC (collagen-like Alzheimer amyloid plaque component), was identified using antibodies raised against insoluble amyloid fr...

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α-Helical Coiled-coil Oligomerization Domains Are Almost Ubiquitous in the Collagen Superfamily

Cited by 78 publications

References 66 publications

A conserved trimerization motif controls the topology of short coiled coils

A conserved trimerization motif controls the topology of short coiled coils

Multimeric Amphipathic α‐Helical Sequences for Rapid and Efficient Intracellular Protein Transport at Nanomolar Concentrations

Characterization of the Alzheimer's Disease-associated CLAC Protein and Identification of an Amyloid β-Peptide-binding Site

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