Protein subunit interfaces: heterodimers versus homodimers

Zhanhua, Cui; Gan, Jacob Gah-Kok; Lei, Li; Sakharkar, Meena Kishore; Kangueane, Pandjassarame

doi:10.6026/97320630001028

Cited by 56 publications

(57 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2) in 2S (r 2 = 0.41) and 3SMI (r 2 = 0.52). The data presented here for 2S and 3SMI is different from the relation shown by Zhanhua et al [12]. However, this is not true for 3SDI Fig.…”

Section: Discussioncontrasting

confidence: 69%

See 1 more Smart Citation

Structural features for homodimer folding mechanism

Lulu¹,

Suresh²,

Karthikraja³

et al. 2009

Journal of Molecular Graphics and Modelling

Self Cite

View full text Add to dashboard Cite

“…2) in 2S (r 2 = 0.41) and 3SMI (r 2 = 0.52). The data presented here for 2S and 3SMI is different from the relation shown by Zhanhua et al [12]. However, this is not true for 3SDI Fig.…”

Section: Discussioncontrasting

confidence: 69%

“…A study by Zhanhua et al showed the weak relationship of monomer length with interface area (r 2 = 0.20) and interface residues (r 2 = 0.23) in a large dataset of 170 homodimers [12]. Therefore, it is of interest to study similar relationships within the 2S, 3SMI and 3SDI subsets.…”

Section: Discussionmentioning

confidence: 96%

Structural features for homodimer folding mechanism

Lulu¹,

Suresh²,

Karthikraja³

et al. 2009

Journal of Molecular Graphics and Modelling

Self Cite

View full text Add to dashboard Cite

“…The mutant TNSALP enzymes produced have variable and possibly preferential catalytic activity of substrates, inorganic pyrophosphate, and PLP (Di Mauro et al 2002). The mutant enzymes are also often found as heterodimers which have variable catalytic activity depending on the combination of monomers composing that particular heterodimeric enzyme (Di Mauro et al 2002;Zhanhua et al 2005). These characteristics of TNSALP produced in those with mutations of the TNSALP gene help explain some of the phenotypic variability of disease in HPP.…”

Section: Discussionmentioning

confidence: 99%

Infantile Hypophosphatasia Secondary to a Novel Compound Heterozygous Mutation Presenting with Pyridoxine-Responsive Seizures

et al. 2013

View full text Add to dashboard Cite

Hypophosphatasia (HPP) is a rare metabolic disease with the hallmark finding of deficient serum tissue nonspecific alkaline phosphatase (TNSALP) activity. TNSALP is primarily known for its role in mineralization; hence, HPP is characterized by defective mineralization of bone and/or teeth. TNSALP is also necessary for proper vitamin B6 metabolism and its participation as a cofactor for neurotransmitters in the central nervous system. Defective TNSALP activity in the brain can result in intractable seizures responsive to pyridoxine. The pathophysiology of pyridoxine-responsive seizures (PRS) in severe HPP remains to be clearly defined. We review the case of a 2-month-old Caucasian boy presenting with seizures refractory to conventional antiepileptic medications. Empiric treatment with favorable response to pyridoxine in conjunction with severe metabolic bone disease, extremely low serum alkaline phosphatase, elevated phosphoethanolamine, hypercalcemia, hypercalciuria, and nephrocalcinosis led to a clinical diagnosis of infantile HPP. Sequence analysis revealed compound heterozygosity of the TNSALP gene with a novel mutation in exon 9 and a previously reported mutation in exon 12. This case reminds the physician that severe infantile HPP can present with PRS as its major initial manifestation and should alert clinicians to consider HPP in their differential of PRS. In addition, despite this severe genotype, the clinical diagnosis of our patient was delayed because of minimal phenotypic features initially. This highlights that the phenotypegenotype correlation could be variable even in severe disease. This case also demonstrates that HPP should be classified as PRS and not a form of pyridoxine-dependent epilepsy (PDE) as our patient was able to stop the pyridoxine supplementation without seizure recurrence once enzyme replacement was initiated. With the advent of enzyme replacement therapy, this once fatal disease may have improved morbidity and mortality.

show abstract

“…While we could not determine if oligomer formation was due to misfolding or nonspecific association, we may have been at high risk of nonspecific association when using cysteines, which are hydrophobic, to coordinate zinc at a hydrophobic interface. Previous studies have shown that homodimeric interfaces tend to be more hydrophobic than heterodimeric interfaces 46 , though perhaps more polar character would help us avoid high-order nonspecific oligomerization in future designs.…”

Section: Discussionmentioning

confidence: 99%

Metal-Mediated Affinity and Orientation Specificity in a Computationally Designed Protein Homodimer

et al. 2011

View full text Add to dashboard Cite

Computationally designing protein-protein interactions with high affinity and desired orientation is a challenging task. Incorporating metal-binding sites at the target interface may be one approach for increasing affinity and specifying the binding mode, thereby improving robustness of designed interactions for use as tools in basic research as well as in applications from biotechnology to medicine. Here we describe a Rosetta-based approach for the rational design of a protein monomer to form a zinc-mediated, symmetric homodimer. Our metal interface design, named MID1 (NESG target ID OR37), forms a tight dimer in the presence of zinc (MID1-zinc) with a dissociation constant <30 nM. Without zinc the dissociation constant is 4 μM. The crystal structure of MID1-zinc shows good overall agreement with the computational model, but only three out of four designed histidines coordinate zinc. However, a histidine-to-glutamate point mutation resulted in four-coordination of zinc, and the resulting metal binding site and dimer orientation closely matches the computational model (Cα RMSD = 1.4 Å).

show abstract

Protein subunit interfaces: heterodimers versus homodimers

Cited by 56 publications

References 18 publications

Structural features for homodimer folding mechanism

Structural features for homodimer folding mechanism

Infantile Hypophosphatasia Secondary to a Novel Compound Heterozygous Mutation Presenting with Pyridoxine-Responsive Seizures

Metal-Mediated Affinity and Orientation Specificity in a Computationally Designed Protein Homodimer

Contact Info

Product

Resources

About